delayed dentition

SHORT Syndrome

Clinical Characteristics
Ocular Features: 

Deeply set eyes are frequently noted and perhaps are a result of the lipodystrophy.  Anterior segment abnormalities resembling Rieger anomalies are often associated with congenital glaucoma. 

Systemic Features: 

There is considerable clinical heterogeneity.  The facial gestalt, however, is said to be characteristic.  These are: triangular progeroid facies with a prominent forehead, absence of facial fat, midface hypoplasia, and hypoplastic nasal alae.  Insulin resistance seems to be a consistent feature as well and nephrocalcinosis is common.  Serum and urinary calcium may be elevated even in infancy.

Teeth are late to erupt and bone age is delayed with shortness of stature the final result in many cases.  Joints are often hyperextensible.  A neurosensory hear loss has been found in some individuals.  Notably, developmental milestones are usually timely although mild cognitive delays are rarely seen and speech may be delayed.  Inguinal hernias are part of the syndrome. 

Genetics

Heterozygous mutations in the PIK3R1 gene (5q31.1) are responsible for this syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Serum and urinary calcium should be monitored.  The risk of glaucoma is high and patients should be monitored and treated appropriately.  Blood sugar and insulin levels may require treatment.  Inguinal hernias may require surgical repair.

References
Article Title: 

Mutations in PIK3R1 cause SHORT syndrome

Dyment DA, Smith AC, Alcantara D, Schwartzentruber JA, Basel-Vanagaite L, Curry CJ, Temple IK, Reardon W, Mansour S, Haq MR, Gilbert R, Lehmann OJ, Vanstone MR, Beaulieu CL; FORGE Canada Consortium., Majewski J, Bulman DE, O'Driscoll M, Boycott KM, Innes AM. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013 Jul 11;93(1):158-66. 

PubMed ID: 
23810382

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: 

Barber-Say Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features consist mainly of skin changes in the lids including hyperlaxity and redundancy.  There may be ectropion of the lower eyelids and sparsity of the eyebrows.  Some evidence of micro- or ablepharon is often present.  Hypertelorism and exophthalmia have been described.

Systemic Features: 

Multiple external congenital anomalies are present at birth including skin laxity, hypertrichosis (especially of the forehead, neck and back), and low-set and malformed pinnae.  Macrostomia and thin lips with redundant facial skin are often evident.  The nose appears bulbous.  The thoracic skin can be atrophic and the nipples may be hypoplastic.  Hypospadias has been reported.  A highly arched or cleft palate may be present and some individuals have a conductive hearing loss.  The teeth are small and eruption may be delayed.  Cognitive deficits may be present and mental retardation has been reported. 

Genetics

Based on genotyping and the limited number of reported pedigrees, inheritance most likely follows an autosomal dominant pattern.  Direct parent to child transmission has been reported.  Detailed examination of parents sometimes reveals mild features that are easily missed.  Mutations in the TWIST2 gene have been found in 10 unrelated individuals with Barber-Say syndrome.

TWIST2 mutations have also been found in Setleis syndrome (227260) and in ablepharon-macrostomia syndrome (200110).  These conditions have some clinical features in common with Barber-Say syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment for this disorder but correction of selected anomalies such as ectropion and cleft palate may be indicated.

References
Article Title: 

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, Huang H, Valkanas E, Pusey B, Schanze D, Venselaar H, Vulto-van Silfhout AT, Wolfe LA, Tifft CJ, Zerfas PM, Zambruno G, Kariminejad A, Sabbagh-Kermani F, Lee J, Tsokos MG, Lee CC, Ferraz V, da Silva EM, Stevens CA, Roche N, Bartsch O, Farndon P, Bermejo-Sanchez E, Brooks BP, Maduro V, Dallapiccola B, Ramos FJ, Chung HY, Le Caignec C, Martins F, Jacyk WK, Mazzanti L, Brunner HG, Bakkers J, Lin S, Malicdan MC, Boerkoel CF, Gahl WA, de Vries BB, van Haelst MM, Zenker M, Markello TC. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. Am J Hum Genet. 2015 Jul 2;97(1):99-110.

PubMed ID: 
26119818

Tenorio Syndrome

Clinical Characteristics
Ocular Features: 

The eyebrows appear bushy.  Inflammation of the limbus and keratoconjunctivitis sicca are often present and reported to resemble Sjogren syndrome.

Systemic Features: 

Infants appear large at birth with a large forehead and macrocephaly.  Birth weight, length, and head circumference are usually above the 97th percentile. The mandible appears large and the lips are full and ‘fleshy’.  Dentition is delayed.  Recurrent stomatitis and gastroesophageal reflux have been noted.  Closure of the fontanels is delayed.  Hypotonia and hyperflexible joints can be a feature.

Multiple brain anomalies have been described including cortical atrophy, dilated and asymmetrical ventricles, and mild hydrocephalus.  Psychomotor development and milestones are delayed.  Intellectual disabilities, syncope, hypoglycemia, seizures, apneic episodes, mood anomalies, abnormal gait, and general clumsiness may be present.  There was considerable clinical variation among the six reported patients. 

Genetics

Heterozygous mutations in RNF125 (18q12.1) are responsible for this syndrome. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

A new overgrowth syndrome is due to mutations in RNF125

Tenorio J, Mansilla A, Valencia M, Martinez-Glez V, Romanelli V, Arias P, Castrejon N, Poletta F, Guillen-Navarro E, Gordo G, Mansilla E, Garcia-Santiago F, Gonzalez-Casado I, Vallespin E, Palomares M, Mori MA, Santos-Simarro F, Garcia-Minaur S, Fernandez L, Mena R, Benito-Sanz S, del Pozo A, Silla JC, Ibanez K, Lopez-Granados E, Martin-Trujillo A, Montaner D; SOGRI Consortium, Heath KE, Campos-Barros A, Dopazo J, Nevado J, Monk D, Ruiz-Perez VL, Lapunzina P. A new overgrowth syndrome is due to mutations in RNF125. Hum Mutat. 2014 Dec;35(12):1436-41.

PubMed ID: 
25196541

CODAS Syndrome

Clinical Characteristics
Ocular Features: 

Dense nuclear cataracts can be seen by six months of age.  Some patients have ptosis. The fundi have been described as normal at one month of age in a single infant but vision was described at the 20/200 level at 2 years of age.  Cataracts noted at 4 months had been removed.

Systemic Features: 

Patients have multiple severe systemic abnormalities.  There is generalized developmental delay along with mild microcephaly and hypotonia.   The forehead is often broad while the face appears flattened with anteverted nares, a flat nasal bridge, a short philtrum, low-set and crumpled ears.  Infants may have an inadequate upper respiratory apparatus with atrophic vocal cords and some die of laryngeal obstruction in the first days of life.  Sialorrhea and difficulty swallowing have been noted.  Mild to moderate neurosensory hearing loss is often present but there may also be a conduction component to this. 

Brain imaging has revealed large ventricles, with subcortical hypomyelination, a thin corpus callosum, and prominent cortical sulci.  The vertebrae may have coronal clefts and scoliosis often develops. Generalized metaphyseal dysplasia and delayed bone age are usually present.  The anus may be imperforate and a rectovaginal fistula and cryptorchidism have been reported.  Long bones may be malformed as well and most patients are short in stature. Delayed dentition, enamel dysplasia, and abnormal cusp morphology are often present.  Cardiac septal defects may be seen.

Genetics

Homozygous mutations in LONF1 (19p13.3) segregate with the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no general treatment available and infants sometimes die from laryngeal obstruction in the first days of life.   Individual anomalies may be surgically correctable in selected individuals.  Occasional infants are stillborn but one patient died an accidental death at 14 years of age. 

References
Article Title: 

CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease

Strauss KA, Jinks RN, Puffenberger EG, Venkatesh S, Singh K, Cheng I, Mikita N, Thilagavathi J, Lee J, Sarafianos S, Benkert A, Koehler A, Zhu A, Trovillion V, McGlincy M, Morlet T, Deardorff M, Innes AM, Prasad C, Chudley AE, Lee IN, Suzuki CK. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am J Hum Genet. 2015 Jan 8;96(1):121-35.

PubMed ID: 
25574826

Microphthalmia, Syndromic 2

Clinical Characteristics
Ocular Features: 

Microphthalmia with congenital cataracts are the outstanding ocular features of this syndrome.  Some patients have glaucoma.  Blepharophimosis, ptosis, and ankyloblepharon have also been reported.

Systemic Features: 

Facial dysmorphism, dental anomalies and cardiac defects are consistently present.  The face may appear elongated while the nose can be short with a broad tip and long philtrum.  The primary teeth often persist into the second decade but oligodontia, hyperdontia, and dental radiculomegaly may be seen as well.  Reported cardiac defects include ASD, VSD and floppy valves.  Some patients have cleft palate.  Renal, and intestinal malformations have also been described and some patients exhibit psychomotor delays.

Genetics

This is an X-linked disorder secondary to a mutation in the BCOR gene at Xp11.4.  Because virtually all patients are female, it has been suggested that this is an X-linked dominant mutation with lethality in hemizygous males (mother-daughter transmission has been reported).  This is one of several disorders [others being Incontinentia pigmenti (308300)and focal dermal hypoplasia (305600)] in which skewed X-chromosome inactivation has been demonstrated.

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

Cataracts can be removed and glaucoma requires treatment.

References
Article Title: 
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