Hypoparathyroidism-Retardation-Dysmorphism Syndrome

Alternative Names

  • HRD
  • Hypoparathyroidism with Short Stature, Mental Retardation, and Seizures
  • Sanjad-Sakati Syndrome
  • SSS
  • Hypoparathyroidism, Congenital, Associated with Dysmorphism, Growth Retardation, and Developmental Delay
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WHO-ICD-10 version:2010

Endocrine, nutritional and metabolic diseases

Disorders of other endocrine glands

OMIM Number

241410

Mode of Inheritance

Autosomal recessive

Gene Map Locus

1q42-q43

Description

Sanjad Sakati Syndrome (also known as hypoparathyroidism-retardation-dysmorphism syndrome or HRD) is a rare autosomal recessive genetic defect. As its name suggests, this condition is characterized by congenital hypoparathyroidism, intrauterine and postnatal growth retardation, mental retardation, and dysmorphic features, including microcephaly, retromicrognathia, deep-set eyes, depressed nasal bridge, large and floppy ear lobes, and abnormal dentition. Affected patients also present with hypocalcemia, hyperphosphatemia, and in some cases, low concentration of immuno-reactive parathyroid hormone. The clinical features are very similar to the autosomal recessive form of Kenny-Caffey syndrome (KCS), except for the lack of osteosclerosis and recurrent bacterial infections present in the latter.

The exact incidence of this syndrome is not known. However, the condition has been found to be almost exclusively limited to Arab children particularly of Bedouin origin.

Molecular Genetics

Linkage analysis and further fine mapping and mutational studies have identified that mutations in the Tubulin Specific Chaperone E (TBCE) gene are responsible for HRD. This gene is responsible for encoding one of the many chaperone proteins involved in the folding of the alpha-tubulin subunits for the tubulin heterodimers. Cofactor E is responsible for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Thus, cofactor E defect may alter trafficking, signal transduction, and/or cellular migration, and would interfere with tubulin assembly. In fact, microscopic analysis of microtubules in affected cells has shown lowered density and disturbed microtubule polarity, as well as abnormalities in membrane trafficking. Interestingly, it has also been shown that both HRD and the autosomal recessive form of KCS arise from mutations in the same TBCE gene, indicating that these two diseases may actually represent variants of the same disease condition.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
241410.1United Arab EmiratesMaleNoYes Global developmental delay; Failure to t... NM_001079515.2:c.155_166delHomozygousAutosomal, RecessiveSaleh et al. 2021

Other Reports

Oman

Al-Gazali and Dawodu (1997) reported an Omani child with typical features of Sanjad-Sakati syndrome. He was the first child of a highly inbred family. His birth weight was 1.5 kg. At nine months of age, he was first seen because of failure to thrive and repeated attacks of vomiting. On physical examination, he revealed many dysmorphic features like; frontal bossing, deep-set eyes, large abnormal ears with a thin helix, a depressed nasal bridge, and a smooth philtrum. His developmental milestones were delayed, especially the motor milestones. CT scan of the brain showed immature myelination which might indicate that failure to grow was hypothalamic in origin. Bone X-ray displayed osteoporotic changes with increase in cortical thickness of long bones. Alkaline phosphatase and phosphorus levels were elevated, serum calcium level and parathyroid hormone level were reduced, and the liver enzymes were abnormal. These biochemical tests indicated the presence of hypoparathyroidism. It is suggested that the hypothalamus mediates the parathyroid hormone regulation.

Palestine

AbuDraz (2006) reported two unrelated patients from Palestine with HRD. The first was a 5-year old boy who was brought in a state of coma after prolonged tonic-clonic seizures. The patient had previously had several recurrent hospital admissions with convulsions and infections. On examination, the patient was shown to be severely retarded in growth with height, weight and OFC below the 3rd centile, and having dysmorphic facial features with microcephaly, deep set eyes, peaked nose, large discharging ears, and small hands and feet. Laboratory investigation revealed severe hypocalcemia and hyperphosphatemia, but with normal levels of serum alkaline phosphatase and magnesium. Small sized atrial septal defect (ASD) was detectable on echocardiogram. His parents were first cousins, and a sister had died as an infant with chest infection. The patient was treated with calcium supplements and antibiotics. He did not, however, come for follow-up. The second case was that of a girl who had seizures since 12-days of age, and was at that stage found to be severely hypocalcemic. Since the age of 10-months, she had had several hospital admissions with generalized multifocal clonic seizures, vomiting, fever, diarrhea, and dehydration. She was also found to be severely growth retarded and having distinct facies. Lab investigations revealed hypocalcemia, hyperphosphatemia, and low parathyroid hormone. Additionally, nephrocalcinosis was seen on abdominal ultrasound, while small sized ASD was detected by echocardiogram. The girl's parents were second cousins. Three of her siblings had previously died, one at 5-months with hypoparathyroidism, one at 5-months with pneumonia, and one at 35-days to an unknown cause. Treatment was similar to the male patient. Upon follow-up, she was still retarded in her growth, mildly mentally retarded, had poor dentition, and recurrent chest and ear infections.

[AbuDraz A. Sanjad Sakati Syndrome. Palestinian Med J. 2006; 2(1)]

[See also: Saudi Arabia > Padidela et al., 2009].

Qatar

Richardson and Kirk (1990) described eight children (four boys and four girls) with the HRD syndrome with extreme failure to thrive, dysmorphic features, developmental delay, hypoparathyroidism, and abnormal skeletal survey. All patients were born to consanguineous parents, of Middle Eastern origin, and in six of the cases, had at least one similarly affected sibling. Except one child for whom data was not available, all affected children were born underweight (<10th centile), indicating intrauterine growth retardation. Their height and head circumference were also low. All were severely developmentally retarded, with motor milestones severely affected, and speech limited to babbling. Hearing and vision were normal. All patients were hypocalcemic, and low parathyroid hormone was found in six of seven children tested. In fact, five siblings who had died in infancy, were also noted to have been hypocalcemic. Seven of the patients showed medullary stenosis of the long bones. Three presented with septicemia in the neonatal period, and four had reduced number of T lymphocytes. At least three siblings were reported to have died in infancy of overwhelming infection. No chromosomal abnormalities were found on G banding. Among the children was one case who was born in the United Kingdom of first-cousin parents from Qatar. This case presented with dysmorphic features including deep set eyes, beaked nose with depressed nasal bridge, long philtrum with thin upper lip, micrognathia, and large and floppy earlobes. The other children were described simply as being 'of Middle-Eastern origin.' Although some features suggested DiGeorge syndrome or the Kenny-Caffey syndrome, the conclusion was that it indeed represents a separate entity.

Saudi Arabia

Sanjad et al. (1991) reported the case of 12 infants (six boys and six girls), who presented with the first recognized cases of HRD. All patients experienced intrauterine growth retardation, and were underweight when born. Eleven of these patients were born to consanguineous parents, while four had similarly affected siblings. All patients presented with hypocalcemic tetany in the first few days of life, severe growth failure, and psychomotor retardation. Biochemical investigations revealed moderate to severe hypocalcemia and hyperphosphatemia, and low parathyroid hormone concentration in all. Renal function was normal. The patients also had characteristic dysmorphic features, including microcephaly, deep set eyes, thin lips, micrognathia, depressed nasal bridge, beaked nose, and external ear anomalies. Thyroid function studies, growth hormone concentrations, and T and B lymphocyte functions were normal in the patients tested. All patients showed mild to severe mental retardation. CT brain showed mild to moderate ventricular dilation in six patients and intracranial calcification in one. The patients were treated with vitamin D administration, which normalized the biochemical abnormalities. However, the growth failure and psychomotor delay persisted. Four patients died during the period of study. Sanjad et al. (1991) considered this to be a new syndrome, distinct from DiGeorge syndrome. Since seven of the 12 affected families came from the Western region of Saudi Arabia, they also suggested that the mutation responsible for the condition could have originated from that area.

Kalam and Hafeez (1992) described a 4-year-old Saudi female with extreme failure to thrive, striking dysmorphic features, congenital hypoparathyroidism, developmental delay, UTI, seizures, chronic otitis media, chronic gastroenteritis, and repeated life-threatening infections since birth. Her parents were first cousins. Facial dysmorphic features included frontal prominence, deep-set eyes, depressed nasal bridge, beaked nose, long philtrum, micrognathia, large floppy ears, bifid uvula, and growth retardation.

Marsden et al. (1994) reported a 5.5 year-old Saudi girl with prenatal growth retardation, minor anomalies, hypoparathyroidism, and growth hormone deficiency. Her parents were consanguineous. Primary hypoparathyroidism was indicated because the parathyroid hormone was undetectable, although the renal response to infused parathyroid hormone was normal. Her growth hormone rose to 5.8 ng/ml after arginine stimulation and to 2.3 ng/ml after L-dopa. Following clonidine the growth hormone rose to 15 ng/ml at 120 minutes. She responded normally to infusions of GHRH and TRH. She was treated with recombinant human growth hormone and she showed an increase in height and weight. She was taking 1-alpha-cholecalciferol supplements to control hypocalcemia. The subjects' minor anomalies and delayed development were found to be similar to Saudi subjects suffering from hypothyrodism and growth deficiency. However, considerable differences were found in Kuwaiti children. The subject was treated with human growth hormone and demonstrated an increase in height and weight; also she underwent supplementation with 1-alpha-cholecalciferol to control the hypocalcemia.

Diaz et al. (1999) tested the theory that the recessive form of Kenny-Caffey Syndrome (KCS) is allelic with Sanjad-Sakati Syndrome (SSS) through conducting a study on eight unrelated Saudi SSS cases. The subjects underwent genotyping through polymorphic short tandem repeat markers (STRs) from the SSS/KCS critical region. Multipoint linkage analysis was employed and verified the occurrence of the gene responsible for SSS to the exact chromosomal region like KCS gene, which was defined as 1q42-q43. Furthermore, haplotype analysis was employed on the SSS families and identified the critical region among markers D1S1540 and D1S235. It was found that all cases were homozygous for a rare allele located at marker D1S2649; also most cases were found to be homozygous for a rather uncommon allele at marker D1S235. These two markers describe a conserved haplotype on SSS disease-bearing chromosomes, which were consistent with an ancestral founder mutation. The conserved haplotype was found to be the same as the one spotted in Kuwaiti KCS families, proposing that both syndromes are phenotypic variants resulting from a single ancestral mutation.

Kelly et al. (2000) reported linkage analysis in three consanguineous Saudi Arabian families with Sanjad-Sakati syndrome. A maximum lod score of 4.12 was obtained at D1S235, and analysis of flanking markers D1S1656 and D1S2678 suggested a candidate region of 1 cM. Kelly et al. (2000) noted that Kenny-Caffey syndrome type 1 maps to the same region and suggested that these were likely to be allelic disorders, if not the same condition.

Al-Malik (2004) presented the case of a 4-year-old patient who was referred because of pain in her mouth and poor dental health. Oral findings included micrognathic mandible and maxilla, microdontia, enamel hypoplasia as well as severely decayed teeth. Treatment was carried out under general anesthesia to extract the most severely affected teeth and restore those which could be conserved. It was concluded that these patients have special dental needs; early diagnosis of the affected children is therefore important in order to commence preventive dental therapy and carry out appropriate dental treatment at the optimum time.

Hellani et al. (2004) performed preimplantation genetic diagnosis (PGD) in a family with two affected siblings with SSS. Fluorescent PCR (F-PCR) was utilized to check the heterozygosity and the homozygosity status of the parents and the affected children, respectively. F-PCR was then optimized for single-cell analysis by using peripheral blood lymphocytes. The patient underwent a cycle with intra-cytoplasmic sperm injection. A total of 11 embryos were obtained and biopsied. There were five heterozygous, three homozygous affected and three normal embryos. One heterozygous and one normal embryo were transferred because of their very good quality (morula). A singleton pregnancy was obtained, and amniosynthesis confirmed the presence of the heterozygous fetus. These results show for the first time, the feasibility of PGD for SSS.

Al Tawil et al. (2005) reported female triplets with the clinical and biochemical manifestations of hypoparatyroidism-retardation-dysmorphism (HRD) syndrome also known as Sanjad-Sakati syndrome. They were born for first degree cousins from Saudi Arabia at 35 weeks gestation after assisted pregnancy (in vitro fertilization).

Al Dhoyan et al. (2006) described the ophthalmic manifestations of Sanjad-Sakati syndrome (SSS; hypoparathyroidism-mental retardation-dysmorphism syndrome, HRD) observed in 17 patients who were seen at two hospitals in Riyadh. All 17 of the patients had normal visual acuity. All patients had microphthalmia with normal intraocular pressure. Eight (47%) of the patients had esotropia and four (23%) had exotropia. Ophthalmoscopy revealed tortuous retinal blood vessels in all patients. Hyperopic astigmatism was present in 16 (94%) patients.

Padidela et al. (2009) described two siblings affected with Sanjad-Sakati syndrome. The sisters were born to unrelated parents of Saudi and Palestinian origins. The older girl was 6 years old at the time of examination. In her infancy, she developed profound hypocaolcemia resulting in seizures, and was subsequently diagnosed with hypoparathyrodism. She presented with severe short stature and developmental delay, and dysmorphic features, including a triangular facies, low prominent ears, and delayed dentition. Serum IGF-1 and peak serum GH to glucagon testing were found to be low. Her younger sister had similar features with confirmed hypoparathyrodidism. Serum IGF-1 was undetectably low in her case. Brain MRI of both siblings revealed pronounced microcephaly with reduced white matter bulk and delayed myelination, and severe hypoplasia of the anterior pituitary with a normal posterior pituitary and a hypoplastic infundibulum. A paternal and a maternal cousin of the siblings was also reported to be similarly affected. Keeping in mind the severe hypoplasia of the anterior pituitary, Padidela et al. (2009) suggested that patients with HRD syndrome should be regularly tested for pituitary function for early diagnosis of developing endocrinopathies, such as ACTH.

Tanna et al. (2009) described an 18-year-old Saudi man presenting with respiratory distress.  The patient, born to consanguineous parents, bore features of Sanjad-Sakati syndrome.  These included short stature, microcephaly, retromicrognathia, prominent forehead, and depressed nasal bridge.  He suffered from hypoparathyroidism, calcium deficiency, growth failure and atlantoaxial instability due to which he had to undergo several spinal surgeries.  He also suffered from severe chronic lung disease owing to a small chest cavity, bronchospasm and scoliosis.  Otolaryngologic features included an abnormal dentition with widely spaced teeth, micrognathic mandible and maxilla, and moderate tooth decay; additionally he exhibited a thick neck with a limited range of motion, and a difficult to expose, retroflexed epiglottis with markedly redundant supraglottic mucosa.  The patient had chronic respiratory insufficiency, respiratory distress, and central hypoventilation caused by obstructive sleep apnea.  While he was treated with bilevel positive airway pressure (BiPAP) and received oxygen via a nasal cannula, his blood oxygen saturation level did not improve (86-90%).  Due to this, a tracheostomy was conducted on the patient.

Pal (2010) reported on a Sanjad-Sakati syndrome affected male neonate born to Saudi parents.  The patient was born at 34-weeks via spontaneous vaginal delivery.  By day-4, the infant developed fever, abnormal limb movements, vomiting and clonic seizures in all four limbs.  Facial dysmorphia included microcephaly, deep set eyes, a beaked nose and an abnormal ear.  The patient also had micrognathia along with short hands and feet.  He was found to be hypocalcemic, hypomagnesemic, hypoparathyroidic and hyperphosphatemic.  A blood culture on the 17th day grew klebsiella sp.  Treatment included parenteral calcium, magnesium, pheno-barbitone and antibiotics.  At 22-days of age, the infant was seen to have several abscesses over his shin and fractures of the left humerus and both tibia.  Noting that the fracture sites coincided with the previously attempted IV placement sites, a jugular Hickman catheter was placed to prevent such reoccurrences.  The infant was diagnosed as having SSS and prescribed enteral and parenteral calcium along with vitamin D supplementation.  The authors noted that the fractures took 3-months to heal.   

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