depressed nasal bridge

Al Kaissi Syndrome

Clinical Characteristics
Ocular Features: 

Reported facial dysmorphism features include periocular anomalies of ptosis, hypertelorism, down-slanting lid fissures, and epicanthal folds.  

Systemic Features: 

The phenotype is somewhat variable.  Intrauterine and postnatal growth retardation with hypotonia are common.   Moderate to severe intellectual disability is usually present and speech may be severely delayed.  The forehead is narrow, the nasal tip is broad, the nasal bridge is depressed, and the ears are low-set and posteriorly rotated.   Small hands and sometimes joint laxity are commonly present.  Cervical spine abnormalities including clefting, improper fusion, and segmentation anomalies are common.

Brain MRI may be normal but a small corpus callosum was present in some patients.

Genetics

Homozygous mutations in the CDK10 gene (16q24.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Windpassinger C, Piard J, Bonnard C, Alfadhel M, Lim S, Bisteau X, Blouin S, Ali NB, Ng AYJ, Lu H, Tohari S, Talib SZA, van Hul N, Caldez MJ, Van Maldergem L, Yigit G, Kayserili H, Youssef SA, Coppola V, de Bruin A, Tessarollo L, Choi H, Rupp V, Roetzer K, Roschger P, Klaushofer K, Altmuller J, Roy S, Venkatesh B, Ganger R, Grill F, Ben Chehida F, Wollnik B, Altunoglu U, Al Kaissi A, Reversade B, Kaldis P. CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. Am J Hum Genet. 2017 Sep 7;101(3):391-403.

PubMed ID: 
28886341

Hyperphosphatasia with Mental Retardation Syndrome 6

Clinical Characteristics
Ocular Features: 

Congenital cataracts may be present.  The eyes appear deeply-set and strabismus has been seen in severely affected cases.   

Systemic Features: 

Two families have been reported.  The range of severity in symptoms is wide.  Birth may occur prematurely especially in the presence of polyhydramnios.  Postnatal development can be complicated by seizures, chronic lung disease, developmental regression, and renal disease.  Poor growth secondary to feeding difficulties have been reported.  Death can occur in early childhood.

Dysmorphic features include a short neck, bitemporal narrowing, depressed nasal bridge, and proximal limb shortening.  Osteopenia, flexion contractures, and hip dysplasia may be present.  Dilatation of the renal collecting system with increased echogenicity have been reported.  Creatine kinase and serum alkaline phosphatase may be increased and muscle histology shows small, atrophic fibers with increased fibrosis and considerable variations in fiber size.

Genetics

Homozygous mutations in the PIGY gene (4q22.1) resulting in deficiencies of glycosylphosphatidylinositol synthesis have been associated with this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Ilkovski B, Pagnamenta AT, O'Grady GL, Kinoshita T, Howard MF, Lek M, Thomas B, Turner A, Christodoulou J, Sillence D, Knight SJ, Popitsch N, Keays DA, Anzilotti C, Goriely A, Waddell LB, Brilot F, North KN, Kanzawa N, Macarthur DG, Taylor JC, Kini U, Murakami Y, Clarke NF. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. Hum Mol Genet. 2015 Nov 1;24(21):6146-59.

PubMed ID: 
26293662

Pseudohypoparathyroidism, Type 1A

Clinical Characteristics
Ocular Features: 

Cataracts and nystagmus are sometimes present.  Optic neuritis and papilledema have been reported and can result in optic atrophy.  The combination of cataracts and swelling of the optic nerves in children requires evaluation for hypocalcemia.

Systemic Features: 

The title refers to a group of conditions that have organ resistance to parathyroid hormone.  The phenotype is variable since there usually is a usually some degree of end-organ resistance to other hormones such as gonadotropins and TSH as in the PHP1A disorder described here.  The grouped clinical features are often referred to as Albright hereditary oseodystrophy or AHO.

Short stature with a short neck, a round face, chubby cheeks, and a depressed nasal bridge are usually present.  There may be cognitive deficits and some patients are considered to be mentally retarded.  The fourth and fifth metacarpals and sometimes metatarsals are characteristically short.   The teeth are late to erupt and can have an enamel deficit.  End organ resistance to other hormones may lead to signs of hypothyroidism and hypogonadism.  Calcification of subcutaneous tissues can result in palpable hard nodules and calcium deposition in basal ganglia and choroidal plexus may be demonstrable.  Some patients experience hypocalcemic tetany and seizures.  Hypocalcemia and hyperphosphatemia are often present along with elevated serum parathyroid hormone levels.

Genetics

This transmission pattern is likely modified by the effects of imprinting which also can modify the phenotype.  Mutltigenerational family patterns have an excess of maternal transmission.  The full phenotype is more likely expressed among maternally transmitted cases whereas partial or incomplete expression is more often seen among individuals who received the paternal allele. 

Heterozygous muttions in the GNAS1 gene (20q13.32) plays a role in this disease.  Signal transduction failure likely plays a major role in the failure of organs to respond to the appropriate hormone.

Several subtypes of pseudohypoparathyroidism have been reported but some do not have ocular signs.  However, type 1C (612462) patients can have cataracts and nystagmus with an almost identical phenotype to that of IA and may be the same condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment focuses on normalization of calcium and phosphate serum levels.  A deficiency of vitamin D should also be corrected and has been reported to correct at least some of the lens opacities.  Cataract removal can be considered.

References
Article Title: 

Cataracts, Growth Hormone Deficiency, and Skeletal Dysplasia

Clinical Characteristics
Ocular Features: 

Lens opacities can be seen in infancy or childhood and may be congenital in onset.  Nystagmus has been noted in one patient. 

Systemic Features: 

There is considerable clinical heterogeneity in the phenotype.  Motor milestones may be slightly delayed.  Dysmorphic features in at least some individuals include bushy eyebrows, a prominent forehead, and a small mouth.  Thoracic scoliosis and genu valgum may be present.  Physical growth is reduced during infancy and childhood resulting in a short stature in adulthood.  Growth hormone and cortisol deficiency have been documented. Episodic hypoglycemia has been documented. The pituitary adenohypophysis appears atrophied on MRI.

Neurosensory hearing loss has been diagnosed in the first two years of life.  A distal sensory neuropathy with loss of pain, temperature and touch sensation may be present late in the first decade of life.  There are no cognitive deficits and patients can live independently.

Genetics

This is likely an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the IARS2 gene (1q41).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Appropriate hormonal replacement therapy can be beneficial.  Individual skeletal surgery for scoliosis and hip dislocation should be considered.  Visually significant lens opacities may require surgery.

References
Article Title: 

Mutation in The Nuclear-Encoded Mitochondrial Isoleucyl-tRNA Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome

Schwartzentruber J, Buhas D, Majewski J, Sasarman F, Papillon-Cavanagh S, Thiffaut I, Sheldon KM, Massicotte C, Patry L, Simon M, Zare AS, McKernan KJ; FORGE Canada Consortium, Michaud J, Boles RG, Deal CL, Desilets V, Shoubridge EA, Samuels ME. Mutation in The Nuclear-Encoded Mitochondrial Isoleucyl-tRNA Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness, and Peripheral Neuropathy or with Leigh Syndrome. Hum Mutat. 2014 Nov;35(11):1285-9.

PubMed ID: 
25130867

Craniofacial-Deafness-Hand Syndrome

Clinical Characteristics
Ocular Features: 

This rare syndrome has anomalies in periocular structures but not in the eye itself.  The lid fissures are downward slanting with telecanthus and hypertelorism.  The nasolacrimal duct was missing in several individuals.

Systemic Features: 

The midface is generally flat with underdeveloped maxillary bones and absent or small nasal bones but there may be frontal bossing.  The nose appears hypoplastic with a broad, flat root resulting in dystopia canthorum.  Micrognathia and a high arched palate are sometimes present.   The sinuses are often underdeveloped.  There may be ulnar deviation of the hands and fingers while flexion contractures and clinodactyly of the 5th finger are often present.  A sensorineural hearing loss is present in many individuals.  No poliosis has been reported.

Genetics

This is an autosomal dominant condition secondary to mutations in the PAX3 gene (22q36.1) in at least some patients.  Changes in the same gene are responsible for types 1 and 3 of the Waardenburg syndrome (193500, 148820).  In fact, the major mutation, a heterozygous C-to-G transversion, has been identified in the same codon in both CDHS and Waardenburg 3 (148820) patients.

More patients need to be genotyped to clarify the clinical features distinctive of Waardenburg types 1 and 3 (193500, 148820) and CDHS syndrome.  Should we consider these conditions allelic or simply the result of variable expressivity?  The appearance of the nasal root and associated structures is similar and both conditions are associated with sensorineural hearing loss.  Type 3 Waardenburg syndrome (148820) often has a cleft palate and musculoskeletal deformities of the upper limbs and fingers.  So far, no pigmentation changes have been reported in CDHS.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical release of contractures could be considered.

References
Article Title: 
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