Chromosome 7

BASAL CELL CARCINOMA, SPORADIC (BCC)

Introduction
Basal cell carcinoma occurs most often on areas of the body frequently exposed to the sun the face, ears,
neck, scalp, shoulders, and back. Tumors sometimes develop on areas not often exposed to the sun, but this is rare.
Other contributing factors are exposure to or contact with arsenic or
radiation, or complications from burns, scars, or tattoos.
Basal cell carcinoma sometimes resembles psoriasis or eczema;
therefore, a physician should examine your skin regularly and suggest
regular time intervals for examination depending upon your risk
factors. Watch for changes in size, color, texture, and appearance, as
well as skin pain, bleeding, itching, or inflammation. Common
characteristics of basal cell carcinoma include a bleeding or non-
healing sore, a reddish patch, a shiny bump, a pink growth, or a
scarred area.

Genetic Factors
Mutations in the gene coding for the transmembrane receptor protein PTCH, or PTCH1, are associated with
basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH, the human homolog of
the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway,
which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation)
and regulatory (maintenance of stem cells) roles.
In the resting state, the transmembrane receptor protein PTCH acts catalytically to suppress the seven-
transmembrane protein Smoothened (Smo), preventing further downstream signal transduction. Stoichiometric
binding of the hedgehog ligand to PTCH releases inhibition of Smo, with resultant activation
of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of
angiogenesis. Thus, the balance of PTCH (inhibition) and Smo (activation) manages the essential regulatory
downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH or gain-of-function
mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.
Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the
potential presence of an associated tumor suppressor gene. Further investigation identified a mutation in PTCH that
localized to the area of allelic loss. Up to 30% of sporadic BCCs demonstrate PTCH mutations. In addition to
BCC, medulloblastoma and rhabdomyosarcoma, along with other human tumors, have been associated
with PTCH mutations. All three malignancies are associated with BCNS, and most people with clinical features of
BCNS demonstrate PTCH mutations, predominantly truncation in type.
Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, has been
demonstrated in both BCC and medulloblastoma. PTCH2 displays 57% homology to PTCH1, differing in the
conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal
extension. While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the
hedgehog signaling pathway.
The risk of skin cancer is much higher for whites than for African Americans or Hispanics. This is due to
the protective effect of the skin pigment melanin in people with darker skin. Whites with fair (light-colored) skin
that freckles or burns easily are at especially high risk. This is one of the reasons for the high skin cancer rate in
Australia, where much of the population descends from fair-skinned immigrants from the British Isles. Albinism
is a congenital (present at birth) lack of protective skin pigment. People with this condition may have pink-white
skin and white hair. They have a high risk of getting skin cancer unless they are careful to protect their skin.
The risk of basal and squamous cell skin cancers rises as people get older. This is probably because of the
buildup of sun exposure over time. These cancers are now being seen in younger people as well, probably because
they are spending more time in the sun with their skin exposed.
Chromosome 7
Men are about twice as likely as women to have basal cell cancers and about 3 times as likely to have
squamous cell cancers of the skin. This is thought to be due mainly to higher levels of sun exposure

Epidemiology
Light-colored skin and sun exposure are both important factors in the development of basal cell carcinomas.
About 20% of these skin cancers, however, occur in areas that are not sun-exposed, such as the chest, back, arms,
legs, and scalp. The face, however, remains the most common location for basal cell lesions. Weakening of the
immune system, whether by disease or medication, can also promote the risk of developing basal cell carcinoma.
According to the U.S. National Institutes of Health, ultraviolet (UV) radiation from the sun is the main
cause of skin cancer. Artificial sources of UV radiation, such as sunlamps and tanning booths, can also cause skin
cancer. The risk of developing skin cancer is also affected by where a person lives. People who live in areas that
receive high levels of UV radiation from the sun are more likely to develop skin cancer. In the U.S., for example,
skin cancer is more common in Texas than it is in Minnesota, where the sun is not as strong. Worldwide, the
highest rates of skin cancer are found in South Africa, Israel, New Zealand, and Australia, which are areas that
receive high amounts of UV radiation. Most skin cancers appear after age 50, but the sun's damaging effects begin
at an early age. Therefore, protection should start in childhood in order to prevent skin cancer later in life.

Diagnostic Procedures
Skin biopsy
If the doctor thinks that a suspicious area might be skin cancer, he or she will take a sample of skin from
the area and have it looked at under a microscope. This procedure is called a skin biopsy. If the biopsy removes
the entire tumor, it is often enough to cure basal and squamous cell skin cancers without further treatment.
There are different ways to do a skin biopsy. The doctor will choose one based on the suspected type of
skin cancer, where it is on your body, the size of the affected area, and other factors. Any biopsy is likely to leave
at least a small scar. Different methods may result in different scars, so ask your doctor about possible scarring
before the biopsy is done. No matter which type of biopsy is done, it should remove as much of the suspected area
as possible so that an accurate diagnosis can be made. Skin biopsies are done using a local anesthetic (numbing
medicine), which is injected into the area with a very small needle. You will probably feel a small prick and a little
stinging as the medicine is injected, but you should not feel any pain during the biopsy.

Shave biopsy
For a shave biopsy, the doctor first numbs the area with a local anesthetic. The doctor then shaves off the
top layers of the skin with a small surgical blade. Usually the epidermis and the outer part of the dermis are
removed, although deeper layers can be taken as well if needed. Bleeding from the biopsy site is then stopped by
applying an ointment or a small electrical current to cauterize the wound.

Punch biopsy
A punch biopsy removes a deeper sample of skin. The doctor uses a tool that looks like a tiny round cookie
cutter. Once the skin is numbed with a local anesthetic, the doctor rotates the punch biopsy tool on the surface of
the skin until it cuts through all the layers of the skin, including the dermis, epidermis, and the upper parts of the
subcutis. The edges of the biopsy site are then stitched together.

Incisional and excisional biopsies
To examine a tumor that may have grown into deeper layers of the skin, the doctor may use an incisional
or excisional biopsy. An incisional biopsy removes only a portion of the tumor. An excisional biopsy removes the
entire tumor. After numbing the area with a local anesthetic, a surgical knife is used to cut through the full
thickness of skin. A wedge or sliver of skin is removed for examination, and the edges of the wound are stitched
together.

Chromosome 7
Examining the biopsy samples
All skin biopsy samples are sent to a lab, where they are looked at under a microscope by a pathologist (a
doctor trained in looking at tissue samples to diagnose disease). Often, the samples are sent to a
dermatopathologist, a doctor who has special training in making a diagnosis from skin samples.

Lymph node biopsy
Rarely, when basal or squamous cell skin cancer spreads, it usually goes first to nearby lymph nodes,
which are small, bean-shaped collections of immune cells. If your doctor feels lymph nodes near the tumor that are
too large and/or too firm, a lymph node biopsy may be done to determine whether cancer has spread to them. Fine
needle aspiration biopsy A fine needle aspiration (FNA) biopsy uses a syringe with a thin, hollow needle to
remove very small tissue fragments. The needle is smaller than the needle used for a blood test. A local anesthetic
is sometimes used to numb the area first. This test rarely causes much discomfort and does not leave a scar.
An FNA biopsy is not used to diagnose a suspicious skin tumor, but it may be used to biopsy large lymph
nodes near a skin cancer to find out if the cancer has spread to them. FNA biopsies are not as invasive as some
other types of biopsies, but they may not always provide enough of a sample to find cancer cells.

Surgical (excisional) lymph node biopsy
If an FNA does not find cancer in a lymph node but the doctor still suspects the cancer has spread there, the
lymph node may be removed by surgery and examined. This can often be done in a doctor's office or outpatient
surgical center using local anesthesia and will leave a small scar.


References:
Skin Cancer: Basal Cell Carcinoma (2013, 20 September). Retrieved from
http://www.cap.org/apps/docs/reference/myBiopsy/SkinBasalCellCarcinoma.pdf

Genetics of Skin Cancer (PDQ) (2013). Retrieved from:
http://www.cancer.gov/cancertopics/pdq/genetics/skin/HealthProfessional/page2#Section_12






















Chromosome 7
CRANIOSYNOSTOSIS, TYPE 1

Introduction
Craniosynostosis consists of premature fusion of 1 or more cranial sutures, often resulting in an abnormal
head shape. It may result from a primary defect of ossification (primary craniosynostosis) or, more commonly,
from a failure of brain growth (secondary craniosynostosis). Simple craniosynostosis is a term used when only 1
suture fuses prematurely. Complex or compound craniosynostosis is used to describe premature fusion of multiple
sutures. When children with craniosynostosis, usually complex, also display other body deformities, this is termed
syndromic craniosynostosis.
Symptoms depend on the type of craniosynostosis. They may include: no "soft spot" (fontanelle) on the
newborn's skull, a raised hard ridge along the affected sutures, unusual head shape, and slow or no increase in the
head size over time as the baby grows
Sagittal synostosis (scaphocephaly) is the most common type. It affects the main suture on the very top of
the head. The early closing forces the head to grow long and narrow, instead of wide. Babies with this type tend to
have a broad forehead. It is more common in boys than girls.
Frontal plagiocephaly is the next most common type. It affects the suture that runs from ear to ear on the
top of the head. It is more common in girls.
Metopic synostosis is a rare form that affects the suture close to the forehead. The child's head shape may
be described as trigonocephaly. It may range from mild to severe.
Multiple theories have been proposed for the etiology of primary craniosynostosis, but the most widely
accepted is a primary defect in the mesenchymal layer ossification in the cranial bones.
Secondary craniosynostosis typically results from systemic disorders such as the following:
Endocrine - Hyperthyroidism, hypophosphatemia, vitamin D deficiency, renal osteodystrophy,
hypercalcemia, and rickets
Hematologic disorders that cause bone marrow hyperplasia (eg, sickle cell disease, thalassemia)
Inadequate brain growth, including microcephaly and its causes and shunted hydrocephalus
The syndromic causes appear to result from genetic mutations responsible for fibroblast growth factor
receptors 2 and 3. A gene locus for single suture craniosynostosis has not been identified.[6]
Differentiating plagiocephaly that results from positional molding (which does not require surgery and is
seen frequently) from lambdoid suture fusion is extremely important. The presence of multiple suture fusions
strongly suggests a craniofacial syndrome, which frequently requires the diagnostic expertise of a pediatric
geneticist.
Craniofacial morphogenesis is highly dependent on the patterning information of emigrant cranial neural
crest (CNC) cells. CNC cells give rise to a wide variety of tissues and structures, including skull bones. During
skull development, cranial sutures serve as growth centers for skeletogenesis that is mediated through
intramembranous ossification. This process differs from endochondral ossification in the appendicular and axial
skeletons, where prior formation of cartilage templates is required. Axin2 is highly expressed in CNC cells and
developing sutures neural crest (nasal and frontal bones) but not mesoderm (parietal bones). Dependent
osteogenesis is particularly sensitive to the loss of Axin2.

Genetic Factors
Most cases of syndromic craniosynostosis are caused by one of four genetic mutations. A genetic mutation
occurs when instructions carried in certain genes (a unit of genetic material) become scrambled. This means some
of the body's processes do not work in the normal way.
Examples of mutated genes in craniosynostosis are:
FGFR1, FGFR2 and FGFR3 (three related genes)
TWIST gene
The FGFR group of genes seem to make a protein called fibroblast growth factor receptor work less
effectively. As this protein is involved in regulating cell growth, particularly the growth of bones, it is thought the
FGFR mutation disrupts the development of the skull.
Chromosome 7
The mutated TWIST gene seems to totally block the effects of fibroblast growth factor receptors. There are
often a wide range of birth defects associated with this gene.

Epidemiology
Incidence of craniosynostosis is 0.04-0.1%. Of affected individuals, 2-8% have primary craniosynostosis.
The remaining cases are secondary craniosynostosis, which frequently is accompanied by microcephaly. The
frequencies of the various types of craniosynostosis are as follows: sagittal 50-58%, coronal 20-29%, metopic 4-
10%, and lambdoid 2-4%.
Raised intracranial pressure is rare with fusion of a single suture. It can occur in primary craniosynostosis
when multiple sutures fuse. Primary craniosynostosis: Although the major morbidity is due to the abnormal shape
of the skull, intracranial pressure can be elevated. This occurs with a high frequency in multiple suture synostosis
and rarely with single suture synostosis. Secondary craniosynostosis: Typically no morbidity is noted, except that
related to the underlying disorder. The lack of brain growth often is associated with neurodevelopmental delay.
Craniosynostosis of 1-2 sutures: Cosmetic defect is the primary morbidity.
Craniosynostosis is equally distributed in both boys and girls. Neonatal period: Craniosynostosis is evident
at birth when associated with other craniofacial abnormalities. Infancy (0-18 mo): Secondary or primary
craniosynostosis becomes evident as the child grows.

Diagnostic Procedures

Craniosynostosis can usually be diagnosed by a paediatrician
(specialist in treating children) after a visual examination of your baby's
head. Any severe distortions of the skull or face will be apparent, and
the existence of ridges over fused sutures or misalignment of the ears
will also provide evidence of craniosynostosis. An X-ray of the skull
may be taken to confirm a diagnosis of craniosynostosis.
A computerised tomography (CT) scan is the most detailed
method of assessing the condition of your child's skull. A CT scan
involves taking a series of X-rays and using a computer to reassemble
them into a more detailed image. CT scans are usually only required to plan some types of surgery or if the
diagnosis of craniosynostosis is in doubt.


References:

Craniosynostosis - Causes - NHS Choices. Retrieved September 23, 2013, from
http://www.nhs.uk/Conditions/Craniosynostosis/Pages/Causes.aspx

Jabs EW. Toward understanding the pathogenesis of craniosynostosis through clinical and molecular
correlates. Clin Genet. Feb 1998;53(2):79-86. [Medline].

Kinsman SL, Johnston MV. Craniosynostosis.In: Kliegman RM,Behrman RE, Jenson HB, Stanton BF, eds.
(2011).Nelson Textbook of Pediatrics.19th ed. Philadelphia, Pa: Saunders Elsevier.








Chromosome 7
CURRARINO SYNDROME

Introduction
The Currarino symdrome involves the association of partial sacral agenesis with intact first sacral vertebra
('sickle-shaped sacrum'), a presacral mass, and anorectal malformation . The specific sacral anomaly is distinct to
this syndrome. Associated malformations include rectovaginal fistula, tethering of the cord, duplex ureter,
hydronephrosis, vesicoureteral reflux, bicornuate uterus, and neurogenic bladder. Malignant degeneration of the
presacral teratoma has also been reported.
The term Currarino syndrome is preferred as it is now known that there are other components to this genetic
disorder. Bowel obstruction in infancy or chronic constipation in childhood are the commonest presenting
symptoms. Gynaecological and renal malformation are commonly described. Hirschsprungs disease and meningitis
(often E Coli ascending meningitis) have been recorded. Perianal sepsis, which is found in at least 10% of patients,
can indicate the presence of an underlying presacral mass. Tumour development within the teratoma has been
documented. A report describing Currarino syndrome
with ventriculomegaly due to a Arnold-Chiari type II
malformation must be interpreted with caution. The
affected child was dysmorphic with hypertelorism, a
short enlarged neck and camptodactyly. The mother and
brother also had Currarino syndrome without these
added features. It is quite possible that this child had two
co-existing disorders, one the Currarino inherited from a
mother with typical features and secondly a de novo
Arnold-Chiari type II malformation.
As with many dominant disorders the phenotype
is very variable. It is estimated that approximately 50%
of those who inherit the gene will present with the
severe phenotype (requiring surgery), 25% will have
symptoms albeit milder and 25% will be asymptomatic
heterozygotes.

Genetic Factors
The disorder is an autosomal dominant genetic trait caused by a mutation in the HLXB9 homeobox gene. In
2000 the first large series of Currarino cases was genetically screened for HLXB9 mutations, and it was showed
that the gene is specifically causative for the syndrome, but not for other forms of sacral agenesis

The HLXB9 gene functions as a transcription factor regulating gene expression in both developing and
adult tissues. Little is known about target genes or protein partners.

Epidemiology
Expressivity is variable, which makes it difficult to evaluate the true prevalence of the syndrome: 39% of
patients present with a severe phenotype, 29% are clinically apparent, 28% have X-ray changes only, and 4% are
asymptomatic. Females are more frequently affected, they often have associated gynecological and urinary tract
problems. Age at presentation varies greatly, ranging from birth to 64 years. All first-degree relatives should be
offered a pelvic X-ray. Those with an abnormal x-ray should be referred to a surgeon for further investigation. In a
few cases, deletions of 7q were reported. Prenatal diagnosis is rarely made, and relies on the detection of a
sacrococcygeal mass. Mutational or linkage analysis on fetal cells is possible providing the mutation is known or
the family structure is suitable.



Chromosome 7
Diagnostic Procedures
Cytogenetic analysis will be normal in most cases. However, some cases are associated with a 7q36 deletion or a
translocation involving this region. It is worth considering FISH analysis of 7q36 in cases where Currarino
syndrome is associated with developmental delay

In radiologic test, The first sacral vertebra is not affected, and the hemi-sacrum below usually takes the form of a
sickle or crescent with the so-called scimitar sign at X-rays.


Reference:

GeneReviews. (2005). Seattle, WA: University of Washington. Available : http://www.ncbi.nlm.nih.gov/books/NBK51784/

Lynch SA . (June 2007) Currarino syndrome. Atlas Genet Cytogenet Oncol Haematol. . Retrived
from: http://AtlasGeneticsOncology.org/Kprones/CurrarinoID10082.html




































Chromosome 7
GREIG CEPHALOPOLYSYNDACTYLY SYNDROME (GCS)

Introduction
Greig cephalopolysyndactyly syndrome is a disorder that affects
development of the limbs, head, and face. The features of this syndrome are
highly variable, ranging from very mild to severe. People with this condition
typically have one or more extra fingers or toes (polydactyly) or an
abnormally wide thumb or big toe (hallux). The skin between the fingers and
toes may be fused (cutaneous syndactyly). This disorder is also characterized
by widely spaced eyes (ocular hypertelorism), an abnormally large head size
(macrocephaly), and a high, prominent forehead. Rarely, affected individuals
may have more serious medical problems including seizures, developmental
delay, and intellectual disability.

Genetic Factors
Mutations in the GLI3 gene cause Greig cephalopolysyndactyly syndrome. The GLI3 gene provides
instructions for making a protein that controls gene expression, which is a process that regulates whether genes are
turned on or off in particular cells. By interacting with certain genes at specific times during development, the
GLI3 protein plays a role in the normal shaping (patterning) of many organs and tissues before birth.
Different genetic changes involving the GLI3 gene can cause Greig cephalopolysyndactyly syndrome. In
some cases, the condition results from a chromosomal abnormalitysuch as a large deletion or rearrangement of
genetic materialin the region of chromosome 7 that contains the GLI3 gene. In other cases, a mutation in
the GLI3 gene itself is responsible for the disorder. Each of these genetic changes prevents one copy of the gene in
each cell from producing any functional protein. It remains unclear how a reduced amount of this protein disrupts
early development and causes the characteristic features of Greig cephalopolysyndactyly syndrome.

Epidemiology
This condition is very rare; its prevalence is unknown.

Diagnostic Procedures

1. Cytogenetic analysis. Giemsa-banding karyotype performed at the 500-600 band level with attention
directed to 7p13 detects atranslocation or interstitial deletion in fewer than 5%-10% of affected individuals
Note: Giemsa-banded karyotypes do not detect all deletions, even those on the order of 1 Mb [unpublished
observations].

2. Molecular Genetic Testing. GLI3 is the only gene in which mutation isknown to be associated with Greig
cephalopolysyndactyly syndrome.

3. Clinical testing
a. Sequence analysis detects mutations in approximately 70% of typically affected individuals
b. Duplication/deletion testing.
i. FISH analysis using hybridization of the labeled BAC clone to metaphase spreads detects
deletions in the estimated 5%-10% of individuals with large deletions
ii. Array comparative genomic hybridization (array CGH) of GLI3. No data have been
published on use of this method to detect GLI3 deletions but it is reasonable to expect that
array CGH would detect a deletion that encompasses more than one target on the array.
Chromosome 7
iii. MLPA (multiplex ligation-dependent probe amplification). The general utility of MLPA is
well established; however, no data demonstrating the specificity or sensitivity of this
technique for GLI3 deletions or duplications have been published.

4. Research testing. Molecular genetic testing is complicated by the wide spectrum of mutations that are
known to cause GCPS. Current methodology includes the following:
a. Sequence analysis
b. Loss-of-heterozygosity (LOH) analysis to detect large deletions
c. qPCR
d. Array CGH

References:

GeneReviews. (2005). Seattle, WA: University of Washington. Available :
http://www.ncbi.nlm.nih.gov/books/NBK51784/

Greig cephalopolysyndactyly syndrome - Genetics Home Reference. (n.d.). Retrieved September 23, 2013, from
http://ghr.nlm.nih.gov/condition/greig-cephalopolysyndactyly-syndrome

































Chromosome 7
HOLOPROSENCEPHALY

Introduction
Holoprosencephaly is a disorder caused by the failure of the prosencephalon (the embryonic forebrain) to
sufficiently divide into the double lobes of the cerebral hemispheres. The result is a single-lobed brain structure and
severe skull and facial defects. In most cases of holoprosencephaly, the malformations are so severe that babies die
before birth. In less severe cases, babies are born with normal or near-normal brain development and facial
deformities that may affect the eyes, nose, and upper lip.
There are three classifications of holoprosencephaly. Alobar, in which the brain has not divided at all, is
usually associated with severe facial deformities. Semilobar, in which the brain's hemispheres have somewhat
divided, causes an intermediate form of the disorder. Lobar, in
which there is considerable evidence of separate brain
hemispheres, is the least severe form. In some cases of lobar
holoprosencephaly the baby's brain may be nearly normal.
The least severe of the facial anomalies is the median cleft
lip (premaxillary agenesis). The most severe is cyclopia, an
abnormality characterized by a single eye located in the area
normally occupied by the root of the nose, and a missing nose or a
proboscis (a tubular-shaped nose) located above the eye. The least
common facial anomaly is ethmocephaly,in which a proboscis
separates closely-set eyes. Cebocephaly, another facial anomaly,
is characterized by a small, flattened nose with a single nostril
situated below incomplete or underdeveloped closely-set eyes.

Genetic Factors
Mutations in 11 genes have been found to cause nonsyndromic holoprosencephaly. These genes provide
instructions for making proteins that are important for normal embryonic development, particularly for determining
the shape of the brain and face. About 25 percent of people with nonsyndromic holoprosencephaly have a mutation
in one of these four genes: SHH, ZIC2, SIX3, or TGIF1. Mutations in the other genes related to nonsyndromic
holoprosencephaly are found in only a small percentage of cases. Many individuals with this condition do not have
an identified gene mutation. The cause of the disorder is unknown in these individuals.
The brain normally divides into right and left hemispheres during the third to fourth week of pregnancy. To
establish the line that separates the two hemispheres (the midline), the activity of many genes must be tightly
regulated and coordinated. These genes provide instructions for making signaling proteins, which instruct the cells
within the brain to form the right and left hemispheres.
Signaling proteins are also important for the formation of the eyes. During early development, the cells that
develop into the eyes form a single structure called the eye field. This structure is located in the center of the
developing face. The signaling protein produced from the SHH gene causes the eye field to separate into two
distinct eyes. The SIX3 gene is involved in the formation of the lens of the eye and the specialized tissue at the back
of the eye that detects light and color (the retina).
Mutations in the genes that cause nonsyndromic holoprosencephaly lead to the production of abnormal or
nonfunctional signaling proteins. Without the correct signals, the eyes will not form normally and the brain does
not separate into two hemispheres. The development of other parts of the face is affected if the eyes do not move to
their proper position. The signs and symptoms of nonsyndromic holoprosencephaly are caused by abnormal
development of the brain and face.
Researchers believe that other genetic or environmental factors, many of which have not been identified,
play a role in determining the severity of nonsyndromic holoprosencephaly.

Chromosome 7
Epidemiology
Holoprosencephaly has an estimated birth prevalence rate of approximately 1 in 10,000 births. This is likely
to be an underestimation owing to recognition of milder cases later in life.
Holoprosencephaly occurs worldwide. Reported frequency rates of holoprosencephaly have wide variations
depending on the study design. The rates are higher if terminations of pregnancy are included. The frequency
among all pregnancies has been reported to be 1 in 250 based on a study on embryos obtained through induced
abortion, making this the most common human forebrain malformation.
Ethnic variations have been reported, with a higher birth prevalence among Far East Asians and Filipinos
than in whites in Hawaii and among Pakistanis in Midlands.

However, these may be due to lower prenatal detection
rates in these groups and hence lower rates of pregnancy terminations. Holoprosencephaly has been reported to be
more common in females than in males.

Diagnostic Procedures
Imaging of the brain by CT scan or (preferably) MRI confirms the diagnosis of HPE, may define the
anatomic subtype, and identifies associated CNS anomalies. Approximately 25%-50% of individuals with HPE
have a numeric or structural chromosomal abnormality detectable by chromosome analysis. Approximately 18%-
25% of individuals with monogenic HPE have a recognizable syndrome and the remainder have nonsyndromic
HPE. Molecular genetic testing is possible for many of the genes associated with nonsyndromic HPE.
Approximately 10% of individuals with HPE have defects in cholesterol biosynthesis.


References:

GeneReviews. (2005). Seattle, WA: University of Washington. Available :
http://www.ncbi.nlm.nih.gov/books/NBK51784/

Nonsyndromic holoprosencephaly - Genetics Home Reference. (n.d.). Retrieved September 34, 2013, from
http://ghr.nlm.nih.gov/condition/nonsyndromic-holoprosencephaly























Chromosome 7
LIPOAMIDE DEHYDROGENASE DEFICIENCY (LDD)

Introduction
The DLD gene provides instructions for making a protein called dihydrolipoamide dehydrogenase. This
protein is a part (a subunit) of several enzyme complexes (groups of enzymes that work together). These
complexes are essential for the breakdown of certain molecules to produce energy in cells. Dihydrolipoamide
dehydrogenase forms a subunit called the E3 component that is shared by several enzyme complexes.
Branched-chain alpha-keto acid dehydrogenase, or BCKD, is one of the enzyme complexes that include the
E3 component. The BCKD enzyme complex performs one step in the normal breakdown of three protein building
blocks (amino acids). These amino acidsleucine, isoleucine, and valineare obtained from the diet. They are
present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs. The breakdown of
these amino acids produces molecules that can be used for energy.
The E3 component is also part of the pyruvate dehydrogenase complex. This enzyme complex plays an
important role in the production of energy for cells. It converts a molecule called pyruvate, which is formed from
the breakdown of carbohydrates, into another molecule called acetyl-CoA. The E3 component performs one part of
this chemical reaction. The conversion of pyruvate is essential to begin the series of chemical reactions that
produces adenosine triphosphate (ATP), the cell's main energy source.
The symptoms of dihydrolipoamide dehydrogenase are highly variable and depend on the DLD mutation
even cases caused by two G229C mutations are variable. For some affected individuals with two G229C mutations,
fatigue after exercise may be the only symptom and the condition may go unnoticed until adulthood. In other cases,
symptoms may present in infancy and be severe: recurrent attacks of vomiting, poor muscle tone, poor reflexes,
listlessness, enlarged liver, and seizures. Individuals with two G229C mutations tend to have milder symptoms
than individuals with one G229C mutation in conjunction with another mutation in the DLD gene.

Genetic Factors
Dihydrolipoamide dehydrogenase deficiency is an autosomal recessive disease caused by mutations in
the DLD gene. An individual who inherits one mutation is a carrier and is not expected to have related health
problems. An individual who inherits two mutations in the DLD gene, one from each parent, is expected to be
affected with DLD. If both members of a couple are carriers, the risk for an affected child is 25% in each
pregnancy; therefore, it is especially important that the reproductive partner of a carrier be offered testing.

Epidemiology
DLD is a rare disorder most frequently reported in individuals of Ashkenazi (Eastern European) Jewish
ancestry but occurring in other populations as well. The carrier frequency of DLD in the Ashkenazi Jewish
population is approximately 1/107. Having a relative who is a carrier or is affected can also increase an individuals
risk to be a carrier. Consultation with a genetics health professional may be helpful in determining carrier risk and
appropriate testing. If a gene mutation is identified, an individual should speak to a physician or genetics health
professional about the implications of the result and appropriate testing for the reproductive partner and at-risk
family members.
Diagnostic Procedures
Due to the rarity of the disease, there is no established means of diagnosing the condition. Genetic testing
can reveal if parents are the carrier of the disease. Children are often diagnosed based on a combination of family
history, parental genetic testing and blood tests.
Blood tests are often used to diagnose dihydrolipoamide dehydrogenase deficiency. Since dihydrolipoamide
dehydrogenase deficiency causes the inability to metabolize certain amino acids, high levels of these amino acids in the blood
are indicative of the deficiency. In addition, the blood may have high lactate and episodes of low glucose levels and analysis
of the urine may show a distinct profile of organic acids. Furthermore, genetic testing for DLD mutations is available.
Chromosome 7
References:

Dihydrolipoamide Dehydrogenase Deficiency Inherited Condition - 23andMe. (n.d.). Retrieved September 22,
2013, from https://www.23andme.com/health/dihydrolipoamide-dehydrogenase-deficiency/howitworks/

GeneReviews. (2005). Seattle, WA: University of Washington. Available :
http://www.ncbi.nlm.nih.gov/books/NBK51784/

McKusick VA and Kniffin CL. Dihydrolipoamide dehydrogenase. OMIM Available
at:http://omim.org/entry/248600.









































Chromosome 7
PALLISTER-HALL SYNDROME (PHS)

Introduction
Pallister-Hall syndrome is a disorder that affects the development of many parts of the body. Most people
with this condition have extra fingers and/or toes (polydactyly), and the skin between some fingers or toes may be
fused (cutaneous syndactyly). An abnormal growth in the brain called a hypothalamic hamartoma is characteristic
of this disorder. In many cases, these growths do not cause any medical problems; however, some hypothalamic
hamartomas lead to seizures or hormone abnormalities that can be life-threatening in infancy. Other features of
Pallister-Hall syndrome include a malformation of the airway called a bifid epiglottis, an obstruction of the anal
opening (imperforate anus), and kidney abnormalities. Although the signs and symptoms of this disorder vary from
mild to severe, only a small percentage of affected people have serious complications.

Genetic Factors
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in
each cell is sufficient to cause the disorder. In some cases, an affected person inherits a mutation in theGLI3 gene
from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of
the disorder in their family.
Mutations in the GLI3 gene cause Pallister-Hall syndrome.The GLI3 gene provides instructions for making
a protein that controls gene expression, which is a process that regulates whether genes are turned on or off in
particular cells. By interacting with certain genes at specific times during development, the GLI3 protein plays a
role in the normal shaping (patterning) of many organs and tissues before birth.
Mutations that cause Pallister-Hall syndrome typically lead to the production of an abnormally short
version of the GLI3 protein. Unlike the normal GLI3 protein, which can turn target genes on or off, the short
protein can only turn off (repress) target genes. Researchers are working to determine how this change in the
protein's function affects early development. It remains uncertain how GLI3 mutations can cause polydactyly,
hypothalamic hamartoma, and the other features of Pallister-Hall syndrome.

Epidemiology
This condition is very rare; its prevalence is unknown.

Diagnostic Procedures
The diagnosis of Pallister-Hall syndrome is based on family history and the clinical findings of
hypothalamic hamartoma, central and postaxial polydactyly, bifid epiglottis, imperforate anus, and renal
abnormalities. GLI3 is the only gene in which mutations are known to cause Pallister-Hall syndrome. Pallister-Hall
syndrome (PHS) can be diagnosed based on clinical findings in individuals with classic signs. Molecular genetic
testing may be useful to confirm the diagnosis in these individuals and is used to establish the diagnosis in
individuals in whom the clinical findings are ambiguous or mild.
Major findings are the following:
Hypothalamic hamartoma, a non-enhancing mass in the floor of the third ventricle posterior to the optic
chiasm that is isointense to grey matter on T
1
and T
2
pulse sequences of an MRI, but may have distinct
intensity on FLAIR (Neither cranial CT examination nor cranial ultrasound examination is adequate for
diagnosis of hypothalamic hamartoma.)
Mesoaxial (i.e., insertional or central) polydactyly, the presence of six or more well-formed digits with a
'Y'-shaped metacarpal or metatarsal bone
Chromosome 7
Postaxial polydactyly (PAP) types A and B. PAP-A is the presence of a well-formed digit on the ulnar or
fibular aspect of the limb. PAP-B is the presence of a rudimentary digit or nubbin in the same location.
Postaxial polydactyly is probably more common than mesoaxial polydactyly; however, the nonspecificity
of postaxial polydactyly and the high frequency of postaxial polydactyly type B in persons of central
African descent require caution in its use as a diagnostic feature.
Bifid epiglottis, a midline anterior-posterior cleft of the epiglottis that involves at least two thirds of the
epiglottic leaf. It is a useful feature for clinical diagnosis because it appears to be very rare in syndromes
other than PHS and is also rare as an isolated malformation.
Other. Imperforate anus, renal abnormalities including cystic malformations, renal hypoplasia, ectopic
ureteral implantation, genitourinary anomalies including hydrometrocolpos, pulmonary segmentation
anomalies including bilateral bilobed lungs, and non-polydactyly skeletal anomalies including short limbs
The diagnosis is established in the following individuals:
A proband if mesoaxial polydactyly and hypothalamic hamartoma are present
The first-degree relative of a proband if hypothalamic hamartoma or central or postaxial polydactyly are
present (Postaxial polydactyly type B can be used as a diagnostic criterion for first-degree relatives only in
persons who are not of central African descent.)
Individuals with postaxial (but not mesoaxial) polydactyly and a hypothalamic hamartoma or mesoaxial
polydactyly without hypothalamic hamartoma or hypothalamic hamartoma and other non-polydactyly
malformations should be considered for GLI3sequencing.

References:

Azzam A, Lerner DM, Peters KF, Wiggs E, Rosenstein DL, Biesecker LG. Psychiatric and neuropsychological
characterization of Pallister-Hall syndrome. Clin Genet. 2005 Jan;67(1):87-92.

GeneReviews. (2005). Seattle, WA: University of Washington. Available :
http://www.ncbi.nlm.nih.gov/books/NBK51784/

Pallister-Hall syndrome - Genetics Home Reference. (n.d.). Retrieved September 21, 2013, from
http://ghr.nlm.nih.gov/condition/pallister-hall-syndrome

















Chromosome 7
ARGININOSUCCINICACIDURIA

Introduction
Argininosuccinic aciduria is an inherited disorder that causes ammonia to accumulate in the blood.
Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The
nervous system is especially sensitive to the effects of excess ammonia.
Argininosuccinic aciduria usually becomes evident in the first few days of life. An infant with
argininosuccinic aciduria may be lacking in energy (lethargic) or unwilling to eat, and have poorly controlled
breathing rate or body temperature. Some babies with this disorder experience seizures or unusual body
movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay
and intellectual disability. Progressive liver damage, skin lesions, and brittle hair may also be seen.
Occasionally, an individual may inherit a mild form of the disorder in which ammonia accumulates in the
bloodstream only during periods of illness or other stress.

Genetic Factors
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each
cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the
mutated gene, but they typically do not show signs and symptoms of the condition.
Mutations in the ASL gene cause argininosuccinic aciduria. Argininosuccinic aciduria belongs to a class of
genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occur in liver cells. It
processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is
excreted by the kidneys.
In argininosuccinic aciduria, the enzyme that starts a specific reaction within the urea cycle is damaged or
missing. The urea cycle cannot proceed normally, and nitrogen accumulates in the bloodstream in the form of
ammonia.
Ammonia is especially damaging to the nervous system, so argininosuccinic aciduria causes neurological
problems as well as eventual damage to the liver.

Epidemiology
Argininosuccinic aciduria occurs in approximately 1 in 70,000 newborns.

Diagnostic Procedures
Elevated plasma ammonia concentration (>150 mol/L, sometimes up to 2000-3000 mol/L), elevated
plasma citrulline concentration (usually 200-300 mol/L), and elevated argininosuccinic acid in the plasma or urine
establish the diagnosis of ASL deficiency. Molecular genetic testing of ASL (the only gene in which mutations are
known to be causative) and assay of ASL enzyme activity may be helpful when the biochemical findings are
equivocal. Note: All 50 states in the US include ASL deficiency in their newborn screening programs.

References:

Argininosuccinic aciduria - Genetics Home Reference. (n.d.). Retrieved September 21, 2013, from
http://ghr.nlm.nih.gov/condition/argininosuccinic-aciduria

GeneReviews. (2005). Seattle, WA: University of Washington. Available :
http://www.ncbi.nlm.nih.gov/books/NBK51784/




Chromosome 7
INFANTILE REFSUM DISEASE (IRD)

Introduction
Infantile Refsum disease (IRD) is a medical
condition within the Zellweger spectrum of perixisome
biogenesis disorders (PBDs), inherited genetic disorders
that damage the white matter of the brain and affect
motor movements. PBDs are part of a larger group of
disorders called the leukodystrophies. The Zellweger
spectrum of PBDs include related, but not more severe,
disorders referred to as Zellweger syndrome (ZS) and
neonatal adrenoleukodystrophy. Collectively, these
disorders are caused by inherited defects in any one of 12
genes, called PEX genes, which are required for the
normal formation and function of peroxisomes.
Peroxisomes are cell structures required for the normal
formation and function of the brain, eyes, liver, kidneys,
and bone. They contain enzymes that break down toxic
substances in the cells, including very long chain fatty acids and phytanic acid (a type of fat found in certain
foods), and synthesize certain fatty materials (lipids) that are required for cell function. When peroxisomes are not
functioning, there is over-accumulation of very long chain fatty acids and phytanic acid, and a lack of bile acids
and plasmalogens--specialized lipids found in cell membranes and the myelin sheaths and encase and protect nerve
fibers. IRD has some residual perixisome function, resulting in less severe disease than in Zellweger syndrome.
Symptoms of IRD begin in infancy with retinitis pigmentosa, a visual impairment that oft en leads to blindness,
and hearing problems that usually progress to deafness by early childhood. Other symptoms may include rapid,
jerky eye movements (nystagmus); floppy muscle tone (hypotonia) and lack of muscle coordination (ataxia);
mental and growth disabilities; abnormal facial features; enlarged liver; and white matter abnormalities of brain
myelin. At the mildest extreme of the disorder, intellect may be preserved. Although Adult Refsum disease and
IRD have similar names, they are separate disorders caused by different gene defects.

Genetic Factors
Infantile Refsum disease is an autosomal recessive disorder due to phytanic oxidase deficiency as a result of
mutations in PEX genes 1, 2, and 26. As yet, the exact gene mutation in the Amish has not been identified and only one
family, in Northern Indiana, has been reported. Loci may be at 8q21.1, 7q21-q22, and 22q11.21

Epidemiology
Refsum disease is rare, with just 60 cases published worldwide.
In patients who are untreated or diagnosed late, severe neurological impairment, wasting, and depression
develop, subsequently leading to a high mortality rate. Attenuation of neurologic, ophthalmologic, and cardiac
symptoms requires constant adherence to a suitable diet and plasmapheresis.
No racial predominance is reported.
Only male cases were reported initially; however, now, neither sex predominates.
Classic Refsum disease manifests in children aged 2-7 years; however, diagnosis usually is delayed until
early adulthood. Infantile Refsum disease makes its appearance in early infancy.


Chromosome 7
Diagnostic Procedures
The diagnosis of Refsum disease is suspected on the basis of clinical findings and established by a plasma
phytanic acid concentration greater than 200 mol/L in most affected individuals. Other biochemical findings
include increased phytanic acid/pristanic acid ratio, elevated pipecolic acid concentrations (in 20% of affected
individuals), and deficiency of phytanoyl-CoA hydroxylase enzyme activity or deficiency of the peroxisome-
targeting signal type 2 receptor. Mutations in two genes have been identified in individuals with Refsum
disease: PHYH, the gene that encodes phytanoyl-CoA hydroxylase, is mutated in more than 90% of
individuals; PEX7, the gene that encodes the PTS2 receptor, is mutated in fewer than 10% of individuals.


References:

Bader, P.I., Dougherty, S., Cangany, N., Raymond, G., and Jackson, C.E.: Infantile Refsum disease in four Amish
sibs. Am. J. Med. Genet. 90: 110-114, 2000.

GeneReviews. (2005). Seattle, WA: University of Washington. Available :
http://www.ncbi.nlm.nih.gov/books/NBK51784/

Infantile Refsum Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS).
(n.d.). Retrieved September 22, 2013, from
http://www.ninds.nih.gov/disorders/refsum_infantile/refsum_infantile.htm

Wanders, R.J., Schutgens, R.B., Schrakamp, G, van den Bosch, H., Tager, J.M., Schram, A.W., Hashimoto, T.,
Poll-The, B.T., and Saudubrau, J.M.: Intantile Refsum disease: deficiency of catalases-containing particles
(peroxisomes), alkyldihydroxyacetone phosphate synthase and peroxisomal beta-oxidation enzyme
proteins. Eur. J. Pediatr. 145: 172-175, 1986.

























Chromosome 7
ZELLWEGER SYNDROME

Introduction
The Zellweger spectrum is a group of conditions that have
overlapping signs and symptoms and affect many parts of the body.
This group of disorders includes Zellweger syndrome, neonatal
adrenoleukodystrophy (NALD), and infantile Refsum disease. These
conditions were once thought to be distinct disorders but are now
considered to be part of the same disease spectrum. Zellweger
syndrome is the most severe form of the Zellweger spectrum, NALD is
intermediate in severity, and infantile Refsum disease is the least severe
form. In some cases, it can be difficult to distinguish between the three
conditions that make up the Zellweger spectrum.
Individuals with Zellweger syndrome develop signs and
symptoms of the condition during the newborn period. These infants
experience weak muscle tone (hypotonia), feeding problems, hearing
loss, vision loss, and seizures. These pro blems are caused by the
degeneration of myelin, which is the covering that protects nerves and
promotes the efficient transmission of nerve impulses. The part of the
brain and spinal cord that contains myelin is called white matter.
Destruction of the myelin (demyelination) leads to loss of white matter
(leukodystrophy). Children with Zellweger syndrome also develop life-
threatening problems in other organs and tissues, such as the liver,
heart, and kidneys. They may have skeletal abnormalities, including a
large space between the bones of the skull (fontanels) and characteristic
bone spots known as chondrodysplasia punctata that can be seen with an x-ray. Affected individuals have
distinctive facial features, including a flattened face, broad nasal bridge, and high forehead. Children with
Zellweger syndrome typically do not survive beyond the first year of life.
People with NALD or infantile Refsum disease have more variable features than those with Zellweger
syndrome and usually do not develop signs and symptoms of the disease until late infancy or early childhood. They
may have many of the features seen in more severely affected individuals; however, their condition typically
progresses more slowly. Children with these less severe conditions often have hypotonia, vision problems, hearing
loss, liver dysfunction, developmental delay, and some degree of intellectual disability. Most people with NALD
survive into childhood, and those with infantile Refsum disease may reach adulthood. In rare cases, individuals at
the mildest end of the Zellweger spectrum have developmental delay in childhood and hearing loss or vision
problems beginning in adulthood.

Genetic Factors
Mutations in 12 genes have been found to cause the Zellweger spectrum. These genes provide instructions
for making a group of proteins known as peroxins, which are essential for the formation and normal functioning of
cell structures called peroxisomes. Peroxisomes are sac-like compartments that contain enzymes needed to break
down many different substances, including fatty acids and certain toxic compounds. They are also important for the
production of fats (lipids) used in digestion and in the nervous system. Peroxins assist in the formation (biogenesis)
of peroxisomes by producing the membrane that separates the peroxisome from the rest of the cell and by
importing enzymes into the peroxisome.
Mutations in the genes that cause the Zellweger spectrum prevent peroxisomes from forming normally.
Diseases that disrupt the formation of peroxisomes, including the Zellweger spectrum, are called peroxisome
biogenesis disorders. If the production of peroxisomes is altered, these structures cannot perform their usual
Chromosome 7
functions. The signs and symptoms of Zellweger syndrome are due to the absence of functional peroxisomes within
cells. NALD and infantile Refsum disease are caused by mutations that allow some peroxisomes to form.
Mutations in the PEX1 gene are the most common cause of the Zellweger spectrum and are found in nearly
70 percent of affected individuals. The other genes associated with the Zellweger spectrum each account for a
smaller percentage of cases of this condition.

Epidemiology
Zellweger syndrome is a fatal autosomal recessive disorder. The Zellweger spectrum is estimated to occur
in 1 in 50,000 individuals.


Diagnostic Procedures
The diagnosis can be definitively determined by biochemical assays. Biochemical abnormalities detected in
blood and/or urine should be confirmed in cultured fibroblasts. Measurement of plasma very-long-chain fatty acid
(VLCFA) levels is the most commonly used and most informative initial screen. Elevation of C26:0 and C26:1 and
the ratios C24/C22 and C26/C22 is consistent with a defect in peroxisomal fatty acid metabolism. Mutations in
twelve different PEX genes (PEX1, PXMP3 [PEX2], PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14,
PEX16, PEX19, and PEX26) those that encode peroxins, the proteins required for normal peroxisome assembly
have been identified in PBD, ZSS. Mutations in PEX1, the most common cause of PBD, ZSS, are observed in
about 68% of affected individuals. .



References:

GeneReviews. (2005). Seattle, WA: University of Washington. Available :
http://www.ncbi.nlm.nih.gov/books/NBK51784/

Zellweger spectrum - Genetics Home Reference. (n.d.). Retrieved September 22, 2013, from
http://ghr.nlm.nih.gov/condition/zellweger-spectrum