nephrocalcinosis

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

Pigmentary Retinopathy with Congenital Sideroblastic Anemia

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been fully described, but several patients with a pigmentary retinopathy resembling retinitis pigmentosa have been reported.

Systemic Features: 

Patients present at a median age of two months with typically severe microcytic sideroblastic anemia. Median hemoglobin levels are 7.1 g/dl.  Lymphopenia and panhypogammaglobulinemia are usually present and many children have periodic febrile illnesses.  The number of CD19+ B cells is reduced.  Aminoaciduria, hypercalcinuria, and nephrocalcinosis have been observed.  Cardiomyopathy has been seen in several patients and may be responsible for the early demise.  Developmental delays may be severe with variable neurodegeneration features such as seizures, cerebellar symptoms, and sensorineural hearing loss.  Achievement of milestones is generally delayed.  Median survival is 4 years although one patient has lived to the age of 19 years.

Genetics

Homozygous mutations in TRNT1 (3p25.1) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Allogeneic bone marrow transplantation in one patient reversed the hematologic and immunologic anomalies although retinitis subsequently developed.

References
Article Title: 

Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD)

Chakraborty PK, Schmitz-Abe K, Kennedy EK, Mamady H, Naas T, Durie D, Campagna DR, Lau A, Sendamarai AK, Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Wynn RF, Laxer RM, Minniti CP, Moppett J, Bordon V, Geraghty M, Joyce PB, Markianos K, Rudner AD, Holcik M, Fleming MD. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood. 2014 Oct 30;124(18):2867-71.

PubMed ID: 
25193871

A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)

Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Chakraborty P, Geraghty MT, Major-Cook N, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Fleming MD, Wynn RF. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Blood. 2013 Jul 4;122(1):112-23.

PubMed ID: 
23553769

Blue Diaper Syndrome

Clinical Characteristics
Ocular Features: 

A single patient has been reported with microcornea, optic nerve hypoplasia, and 'abnormal' eye movements.  The full ocular phenotype is unknown but 'visual problems' are sometimes mentioned in other reports.

Systemic Features: 

Nephrocalcinosis and blue urine are the major systemic manifestations of blue diaper syndrome.  Symptoms of fever, constipation, poor weight gain, failure to thrive, and irritability can also be part of the syndrome.

Genetics

This is considered an autosomal recessive disorder although an X-linked defect cannot be ruled out since reported patients have been male.  Parental consanguinity is present in some families.  Nothing is known about the mutation or its locus.  Intestinal transport of tryptophan is defective and bacterial degradation results in excessive indole production.  Oxidation in the urine to indigo blue results in the characteristic discoloration.        

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Restriction of dietary tryptophan has been suggested.

References
Article Title: 
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