Hypoparathyroidism in Complex Disorders (HDR, KSC1/2, HRD, GCLEB)

  • Hypoparathyroidism, sensorineural deafness, renal disease (HDR, OMIM phenotype number #146255)
  • Kenny-Caffey syndrome type 1-2 (KCS1, OMIM phenotype number #244460 ; KSC2, OMIM phenotype number #127000)
  • Hypoparathyroidism, retardation, dysmorphism syndrome (HRD, OMIM phenotype number #241410)
  • Gracile bone dysplasia (GCLEB, OMIM phenotype number #602361)

They include developmental disorders with hypoparathyroidism as a common feature, in which cytogenetic alterations, such as microdeletion 22q11.2 responsible for DiGeorge syndrome, and mutations of PTH, GCM2 and CaSR have been excluded.

They are transmitted as autosomal disorders mainly due to single gene heterozygous mutations and transmitted generally with a dominant pattern of inheritance with some exceptions. Hypoparathyroidism, usually manifesting early in life and due to parathyroid aplasia/hypoplasia, is associated to multiple organ morphological or functional abnormalities. Bone dysplasia may be the main feature.

In the syndrome of hypoparathyroidism, deafness and renal dysplasia (HDR, OMIM phenotype number #146255, also referred to as or Barakat syndrome, or nephrosis, nerve deafness and hypoparathyroidism) early onset hypoparathyroidism, usually manifesting within the first decade of life, is associated with mild-to-severe nephrosis due to renal dysplasia and congenital bilateral sensorineural deafness, with high variable phenotype. It is due to haploinsufficiency of GATA3 (OMIM gene number #131320 on chromosome 10p14), a transcription factor fundamental for the development of the parathyroids, kidney, inner ear, central nervous system, thymus and hematopoietic system. In the parathyroids GATA3 regulates the expression of GCM2, another key gene for parathyroid patterning and function. Mutations/deletions in DNA-binding domain and mutations in regions interacting with additional transcription factors are responsible for the HDR syndrome. No genotype-to-phenotype correlation exists. A specific bone phenotype has not been described, although feature of hypoparathyroidism-related bone disease may be present.

The main feature of Kenny-Caffey syndrome type 1 and 2 (KCS1, OMIM phenotype number #244460; KSC2, OMIM phenotype number #127000) is a bone dysplasia with severe postnatal growth retardation leading to dwarfism, long bones appear small and thin but with thickening of the cortex with medullary stenosis, osteosclerosis of the skull with macrocephaly, eye abnormalities, defective dentition associated with transient/recurrent or permanent hypoparathyroidism. KSC1 is due to mutations in the gene encoding tubulin-specific chaperone E (TBCE; OMIM gene number #604934 on chromosome 1q42.3) and follows a recessive pattern of inheritance, while KSC2 is due to heterozygous mutations in the gene FAM111A (OMIM gene number #615292 on chromosome 11q12.1) and follows an autosomal dominant pattern of inheritance.

The hypoparathyroidism, retardation and dysmorphism syndrome (HRD) (also referred to as Sanjad–Sakati syndrome, OMIM phenotype number #241410) is a disorder characterized by intrauterine growth retardation, mental retardation, congenital hypoparathyroidism with seizures, along with a typical facial dysmorphism (microcephaly, facial and dental anomalies, and small hands and feet), apparently lacking osteosclerosis and inherited in an autosomal recessive manner. It is due to mutations in the same gene whose alterations are responsible for KSC1 (TBCE; OMIM gene number #604934 on chromosome 1q42.3).

Gracile bone dysplasia (GCLEB, or osteocraniostenosis, OCS, OMIM phenotype number #602361) is a severe phenotype with high perinatal lethality in which hypoparathyroidism, developing in the few infants surviving the neonatal period, thin long bones with increased cortex causing medullary stenosis, microphtalmia, triangular face with frontal bossing, premature closure of basal cranial sutures are present. It is caused by mutations in the same gene responsible for KCS-2, namely FAM111A and follows an autosomal dominant pattern of inheritance.

Genes

  • HDR: mutations in GATA3 (OMIM gene number #131320 on chromosome 10p14)
  • KSC1: mutations in TBCE (OMIM gene number #604934 on chromosome 1q42.3)
  • KSC2: mutations in FAM111A (OMIM gene number #615292 on chromosome 11q12.1)
  • HRD: mutations in TBCE (OMIM gene number #604934 on chromosome 1q42.3)
  • GCLEB: mutations in FAM111A (OMIM gene number #615292 on chromosome 11q12.1)

Phenotype

see above

Main biochemical alterations

Low Ca, high Pi, low/undetectable PTH, low 1,25(OH)2D; anemia and low magnesium can be present in KCS and GCLEB

Images

Figure: Phenotypic Features of KCS2 and GCLEB (Unger et al.)

Reproduced from Am J Hum Genet, Vol 92, Unger S, Górna MW, Le Béchec A, et al. FAM111A mutations result in hypoparathyroidism and impaired skeletal development, Pages 990-5, Copyright 2013, with permission from Elsevier.

Other resources

References:

  1. Cianferotti L. and Brandi M.L.: The Molecular Genetics of Hypoparathyroidism. In: The Parathyroids: Basic and Clinical Concepts, Third Edition, Academic Press, 2015.
  2. Nesbit A. Hypoparathyroidism, Deafness and Renal Anomaly Syndrome. In: Hypoparathyroidism, Springer, 2015.
  3. Hershkovitz E. and Parvari R. Hypoparathyroidism, Dwarfism, Medullary Stenosis of Long Bones and Eye Abnormalities (Kenny-Caffey Syndrome) and Hypoparathyroidism, Retardation, and Dysmorphism (Sanjad.Sakati) Syndrome.
  4. Unger S, Górna MW, Le Béchec 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, Bonafé 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.
  5. www.omim.org