hypocalcemia

Gracile Bone Dysplasia

Clinical Characteristics
Ocular Features: 

The eyes have been described as small.  Aniridia may be present.

Systemic Features: 

This is a usually fatal form of skeletal dysplasia with splenic and ocular features as well.  In utero death is not uncommon while newborns may not survive the neonatal period.  The face has been described as dysmorphic with a high forehead, flat nasal bridge, a cloverleaf-shaped skull, and hypoplastic cranial bones with premature suture closure.  The long bones are dysplastic as well with thinned diaphyses (sometimes fractured in utero), growth plate disorganization, excessive remodeling, and signs of arrested growth.  The ribs share in the dysplasia but pulmonary hypoplasia has also been described.  Most individuals have short limbs.

The spleen can be hypoplastic or aplastic and ascites has been noted in several infants.  Failure to thrive is common and seizures have been reported.  Males may have micropenis and hypospadias while females have been described with labial fusion.  

Low parathyroid hormone levels and hypocalcemia has been reported in most individuals.

Genetics

Heterozygous mutations in the FAM111A gene (11q12.1) have been associated with this disorder.  The functional role of FAM111A products is unknown but likely play a role in calcium metabolism, parathyroid hormone secretion, and osseous development.

Mutations in the same gene can be responsible for the allelic autosomal dominant Kenny-Caffey syndrome (127000) with some similar features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

FAM111A mutations result in hypoparathyroidism and impaired skeletal development

Unger S, Gorna MW, Le Bechec A, Do Vale-Pereira S, Bedeschi MF, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E, Magnani C, Nampoothiri S, Nishimura G, Petrella D, Rojas-Ringeling F, Utsunomiya A, Zabel B, Pradervand S, Harshman K, Campos-Xavier B, Bonafe L, Superti-Furga G, Stevenson B, Superti-Furga A. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet. 2013 Jun 6;92(6):990-5.

PubMed ID: 
23684011

Kenny-Caffey Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

Congenital cataracts have been reported in one patient.  There is a report of pseudopapilledema in a 6 year old and another patient has been described with tortuous and dilated retinal vessels.  The hyperopia is likely the result of the small globes.  In an autopsied patient microscopic calcification was noted in the cornea and the retina.

Systemic Features: 

Hypocalcemia and hyperphosphatemia similar to hypoparathyroidism is seen in individuals with KCS2 but it may be transient and self-limited.  Macrocephaly with short stature is characteristic.  Alopecia, delayed closure of the anterior fontanel, and apparent thickening of the cortex in long bones may be seen.  Males have small testicles but there is no evidence regarding fertility.  In an autopsied case no parathyroid tissue could be identified.  Brain imaging may show calcification in the basal ganglia, dentate nuclei, and parts of the cerebrum and cerebellum.  Intelligence is normal.

Genetics

Several heterozygous mutations in the FAM111A gene (11q12.1) have been found.  Many of these seem to be new mutations but there are a number of published families in which there was transmission from mother to child (of both sexes).

Heterozygous mutations in the same gene are responsible for the autosomal dominant  allelic disorder known as Gracile Bone Dysplasia (602361). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Normalization of serum calcium and phosphorous levels would likely be beneficial but complete correction of all the findings is unlikely.  Removal of congenital cataracts should be considered.

References
Article Title: 

FAM111A mutations result in hypoparathyroidism and impaired skeletal development

Unger S, Gorna MW, Le Bechec A, Do Vale-Pereira S, Bedeschi MF, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E, Magnani C, Nampoothiri S, Nishimura G, Petrella D, Rojas-Ringeling F, Utsunomiya A, Zabel B, Pradervand S, Harshman K, Campos-Xavier B, Bonafe L, Superti-Furga G, Stevenson B, Superti-Furga A. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet. 2013 Jun 6;92(6):990-5.

PubMed ID: 
23684011

Ocular findings in Kenny's syndrome

Boynton JR, Pheasant TR, Johnson BL, Levin DB, Streeten BW. Ocular findings in Kenny's syndrome. Arch Ophthalmol. 1979 May;97(5):896-900.

PubMed ID: 
444124

Hypoparathyroidism, Familial Isolated

Clinical Characteristics
Ocular Features: 

Lens opacities may be present.

Systemic Features: 

The major signs and symptoms result from hypocalcemia. Neuromuscular irritability and various paresthesias may be present.  Some patients have  laryngeal spasm and latent tetany with grand mal seizures.  Alopecia, abnormal dentition and coarse brittle hair may be present.  Cognitive deficits and personality disorders are often a feature.  Brain imaging may show calcification of the basal ganglia.  Serum calcium levels are usually low while phosphorus levels are elevated.   Vitamin D precursor levels are usually low or low normal.

Genetics

Familial hypoparathyroidism may be due to mutations in the PTH gene (11p15.3) (either autosomal dominant or recessive inheritance) or in the GCMB gene (6p24.2) (autosomal dominant inheritance pattern).

There is also an X-linked form of hypoparathyroidism (307700) in which parathryroid tissue may be congenitally absent.

A family has been reported in which hypoparathryroidism was associated with lymphedema (247410) and progressive renal failure.  Ptosis, telecanthus, hypertrichosis, restrictive lung disease, and mitral valve prolapse may also be part of the disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Normalization of calcium and phosphorus levels is a priority and this may result in some clearing of the lens opacities.  Cataract surgery may be indicated in selected individuals.

References
Article Title: 

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: 
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