pulmonary hypoplasia

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

Meckel Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype is highly variable.  The globe is often malformed or may be clinically absent.  Cryptophthalmos, clinical anophthalmia, and microphthalmos with sclerocornea and microcornea have been reported.  Posterior staphylomas, retinal dysplasia, partial aniridia, cataracts, and hypoplasia or absence of the optic nerve are sometimes seen.  Some patients have incompletely formed eyes with shallow anterior chambers, angle anomalies, and a persistent tunica vasculosa with lens opacification.  Histopathology may reveal thinning of the nerve fiber layer and a paucity of retinal ganglion cells.  The retina has been described as dysplastic with foci of rosette-like structures and abundant glial cells.

Systemic Features: 

Meckel or Meckel-Gruber syndrome is a clinically and genetically heterogeneous group of disorders with severe multisystem manifestations.  The triad of cystic renal disease, polydactyly (and sometimes syndactyly), and a skull malformation (usually an encephalocele) is considered characteristic of MKS.  However, these signs are variable and only about 60% of patients have all three features.  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones.  Pulmonary hypoplasia is common which, together with kidney and liver disease, is responsible for the poor prognosis of most infants. 

Many clinical abnormalities resemble those present in the Smith-Lemli-Opitz syndrome (270400) and in Joubert syndrome (213300).

Genetics

Most conditions in this group are inherited in an autosomal recessive pattern.  Mutations in 9 genes have been identified as responsible for some variant of MKS in which there is a considerable range of clinical expression.  There is significant clinical overlap with Joubert syndrome and it is not surprising that at least 5 of these mutations have been identified in both conditions.  Further nosological confusion is generated by those who consider patients with the severe, lethal phenotype to have Meckel syndrome while those with milder disease are labeled Joubert syndrome, regardless of genotype.

Rare heterozygotes have been reported with isolated features such as polydactyly.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this syndrome.  The prognosis for life beyond infancy is poor due to the advanced dysfunction of numerous organs such as the kidney, lungs, liver and the central nervous system.

References
Article Title: 

Clinical and genetic heterogeneity in Meckel syndrome

Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, Meusburger H, Tenconi R, Barnicoat A, Winter R, Peltonen L. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997 Nov;101(1):88-92.

PubMed ID: 
9385376

Asphyxiating Thoracic Dysplasia 1

Clinical Characteristics
Ocular Features: 

This is a genetically and clinically heterogeneous condition for which the nosology remains to be worked out.  Not all patients have ocular disease but those who survive infancy may have a pigmentary retinopathy resembling retinitis pigmentosa.  In fact, a 5 year old presented with symptoms of visual loss and night blindness only.  The severeity of the systemic malformations has so far precluded a full description of the ocular phenotype.

Systemic Features: 

The most life-threatening and characteristic systemic feature of ATD is short-ribbed thoracic constriction with respiratory insufficiency.  The chest is small and narrow and sometimes described as bell-shaped.  This deformity can lead to death by asphyxiation, and is a serious risk during infancy.  Other individuals live to adulthood and may have only minimal respiratory difficulties.  Patients who survive childhood can develop cystic renal and hepatic disease.  Pancreatic fibrosis has also been reported.  Brachydactyly and postaxial polydactyly are sometimes present and involve the feet more commonly than the hands.  Short stature secondary to short limbs is frequently noted.

Genetics

Jeune syndrome, or at least some forms of it, is an autosomal recessive condition.  Consanguinity is often present.  A locus (15q13) containing homozygous mutations in ATD has been proposed as one candidate site.  There is considerable genetic heterogeneity with at least 5 types described, all with mutations in different genes.

Another disorder with some similar features causing respiratory distress is Majewski syndrome (263520).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Assisted ventilation can be lifesaving in milder cases.  Thoracic reconstruction has also been helpful in a few individuals.  However, careful patient selection is necessary since some patients have severe pulmonary hypoplasia with underdeveloped alveoli. Ursodeoxycholic acid may slow the progression of the liver disease.

References
Article Title: 
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