Hypoparathyroidism-Retardation-Dysmorphism syndrome (HRDS)

Was ist Hypoparathyroidism-Retardation-Dysmorphism syndrome (HRDS)?

Also known as Sanjad-Sakati syndrome, this rare genetic condition has been found mainly amongst children of parents of Arab descent or ethnicity. These parents are usually related to each other. This makes it extremely rare.

This syndrome is also known as:
HRD Hypoparathyroidism With Short Stature, Mental Retardation, And Seizures Hypoparathyroidism, Congenital, Associated With Dysmorphism, Growth Retardation, And Developmental Delay Sanjad-sakati Syndrome

Was Genveränderungen verursachen Hypoparathyroidism-Retardation-Dysmorphism syndrome (HRDS)?

Veränderungen des TBCE-Gens sind die Ursache des Syndroms. Es wird autosomal-rezessiv vererbt.

Autosomal-rezessive Vererbung bedeutet, dass eine betroffene Person von jedem ihrer Elternteile eine Kopie eines mutierten Gens erhält, wodurch sie zwei Kopien eines mutierten Gens erhält. Eltern, die nur eine Kopie der Genmutation tragen, zeigen im Allgemeinen keine Symptome, haben jedoch eine 25% ige Chance, die Kopien der Genmutationen an jedes ihrer Kinder weiterzugeben.

Was sind die wichtigsten symptome von Hypoparathyroidism-Retardation-Dysmorphism syndrome (HRDS)?

The main symptoms of the syndrome include restricted growth, both before and after birth.

Hypoparathyroidism, with onset in infancy, is another common symptom. It is defined as when the body produces extremely low levels of the hormone, parathroyid. This hormone maintains the minerals, calcium and phosphorus in the body. This in turn causes involuntary muscle cramping and seizures.

Developmental delay and impared intellectual ability is another major symptom of the syndrome.

The unique facial characteristics of the syndrome include delayed growth, a short stature, a small head, deep-set eyes, a depressed nasal bridge, long philtrum, thin upper lip, beaked nose, very small lower jaw and large and floppy earlobes.

Possible clinical traits/features:
Ventriculomegaly, Congenital hypoparathyroidism, Deeply set eye, Cryptorchidism, External ear malformation, Delayed skeletal maturation, Astigmatism, Aplasia/Hypoplasia affecting the eye, Bifid uvula, Convex nasal ridge, Cellular immunodeficiency, Frontal bossing, Prominent forehead, Tetany, Microcephaly, Small hand, Severe intrauterine growth retardation, Recurrent respiratory infections, Recurrent bacterial infections, Spinal canal stenosis, Short palm, Hypoplasia of penis, Hypoparathyroidism, Short foot, Hypocalcemic seizures, Hypocalcemia, Depressed nasal bridge, Hyperphosphatemia, Cognitive impairment, Postnatal growth retardation, Short stature, Opacification of the corneal stroma, High forehead, Patchy osteosclerosis, Thin vermilion border, Seizure, Autosomal recessive inheritance, Posteriorly rotated ears, Micrognathia, Micropenis, Intellectual disability, Intestinal obstruction, Intrauterine growth retardation, Myopathy, Abnormality of dental enamel, Increased bone mineral density

Wie wird jemand getestet? Hypoparathyroidism-Retardation-Dysmorphism syndrome (HRDS)?

Die ersten Tests für das Hypoparathyreoidismus-Retardation-Dysmorphismus-Syndrom können mit einem Screening der Gesichtsanalyse über die FDNA Telehealth Telegenetics-Plattform beginnen, mit der die Schlüsselmarker des Syndroms identifiziert und die Notwendigkeit weiterer Tests aufgezeigt werden können. Eine Konsultation mit einem genetischen Berater und dann einem Genetiker wird folgen.

Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.

Medizinische Informationen zu Hypoparathyroidism-Retardation-Dysmorphism syndrome (HRDS)

Syndrome Overview:
Hypoparathyroidism-retardation-dysmorphism syndrome is characterized by prenatal-onset growth retardation, congenital hypoparathyroidism, hypocalcemic seizures, intellectual disability and craniofacial dysmorphism (deep-set eyes, micrognathia, depressed nasal bridge). Other common features include ophthalmologic abnormalities, dental anomalies and recurrent infections. The autosomal recessive disorder is caused by a homozygous founder mutation in the TBCE gene in mostly Arab populations.

Clinical Description:
Richardson and Kirk (1990) described eight children of Middle Eastern origin with severe failure to thrive, developmental delay and hypoparathyroidism. The eyes were deep-set, the philtrum long, and the earlobes large and floppy. Radiographs revealed medullary stenosis of the long bones in seven cases; a valgus deformity of the femoral neck in two cases; and acro-osteolysis in one case. In four cases tested, there were reduced numbers of T-cell subsets. Multiple affected sibs and parental consanguinity were a feature of the pedigrees.

Sanjad et al., (1991) reported 12 similar cases from Saudi Arabia, and Kalam and Hafeez (1992) reported a further case from the same country.

Marsden et al., (1994) reported a 5 1/2-year-old Saudi girl who presented at 2 weeks of age with hypocalcemic seizures. She was found to have hypoparathyroidism and also growth hormone deficiency. Growth hormone responses to arginine and L-dopa were abnormal; however, after clonidine, the growth hormone response was normal. This was explained by the action of L-dopa on GHRH, whereas clonidine and insulin stimulation appears to result in direct elevation of growth hormone from the pituitary. The authors felt their patient was not as severely retarded as those reported by Richardson and Kirk (1990), and no immunodeficiency was demonstrated.

Hershkovitz et al., (1995) reported cases without T-cell abnormalities.

Shankar et al., (1997) reported a case with somewhat similar features, who also had hypothyroidism and insulin-dependent diabetes. There was progressive developmental delay, blindness, deafness, seizures, and atrophy of the cerebellar and frontal lobes.
Al-Gazali and Dawodu (1997) reported an Omani child with the condition and provide a good review.

Sabry et al., (1999) suggest that this condition is the same as an autosomal recessive form of Kenny-Caffey syndrome (Sabry et al., 1998).

Teebi (2000) suggested the name Sanjad-Sakati syndrome for the condition.

Al-Malik (2004) reviewed the dental findings, which included microdontia and enamel hypoplasia.

Al Dhoyan et al., (2006) looked at 17 Saudi patients from an ophthalmological point of view and found microphthalmia in all, as well as esotropia, exotropia, tortuous retinal vessels and unusual blue-white multicolor flecks in the lens.

Padidela et al., (2009) reviewed the brain MRI and pituitary function testing of six cases with confirmed mutations. All of the cases showed low plasma IGF-I concentration, as well as severe hypoplasia of the anterior pituitary and corpus callosum with decreased white matter bulk. Four of five children tested had subnormal growth hormone.

Albaramki et al., (2012) reviewed the clinical features of eight patients from Jordan, most of whom were found to have the common 12-bp deletion in the TBCE gene.

Haider et al., (2014) reported a case with congenital corneal clouding.

Additional mutation-confirmed cases were described by Ratbi et al., (2015) and Kerkeni et al., (2015).

Prenatal Presentation:
The severe growth retardation associated with this condition usually presents in the prenatal period.

Age of Onset:
Most patients present with hypocalcemic seizures at approximately 2–3 weeks of age (Albaramki et al., 2012).

Molecular genetics:

Parvari et al., (1998) mapped the gene to 1q42-43 in the families reported by Hershkovitz et al., (1995) as well as in newly ascertained families. These authors express some doubt as to whether their families have an identical condition to those reported by Richardson and Kirk (1990).

Diaz et al., (1999) also mapped the gene to 1q24-1q43 in families reported by Sanjad et al., (1991).

Hershkovitz et al., (2000) used linkage analysis for prenatal diagnosis; three normal fetuses and two affected fetuses were detected. Hellani et al., (2004) report on successful preimplantation diagnosis. Al Tawil et al., (2005) reported affected triplets after IVF.
Hypoparathyroidism-retardation-dysmorphism syndrome is caused by a 12-bp deletion in the TBCE gene (c.155-166del12).

Parvari et al., (2001) demonstrated mutations in the TBCE gene in this condition. The gene codes for a chaperone protein required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers.

Most Arab patients with HRDS have a single 12-bp deletion - c.155-166del12 - in the TCFE gene.

Other mutations in TBCE are associated with Kenny-Caffey syndrome and Encephalopathy, progressive, with amyotrophy and optic atrophy.

Ajameh et al., (2018) described a male patient. Novel characteristics included macrocytic anemia treated with folic acid, cow’s milk protein allergy and hypocalcemia with hyperphosphatemia due to hypoparathyroidism (treated with good response).

It should be noted that the condition is likely to be heterogeneous. Courtens et al., (2006) could not find a TBCE mutation in their patient and suggest another locus at 4q35. The diagnosis in the Courtens et al., (2006) paper was questioned by Naguib et al., (2007) but defended by Courtens et al., (2007).

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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