Sanjad-Sakati syndrome

Key points at a glance

Key Points at a Glance

• Sanjad–Sakati syndrome (SSS) is an autosomal recessive disorder caused by TBCE gene mutations, presenting with the triad of congenital hypoparathyroidism, growth retardation, and characteristic facial dysmorphism.
• It is most common in populations with genetic roots in the Arabian Peninsula, with consanguinity being a frequent contributing factor.
• Microphthalmia is the most common ophthalmic finding; retinal vascular tortuosity, band keratopathy, and strabismus are also frequently observed.
• Lifelong calcium and vitamin D supplementation is required, with caution needed to avoid nephrocalcinosis due to overcorrection.
• The same TBCE mutation can also cause Kenny–Caffey syndrome type 1, requiring clinical differentiation.
• Multidisciplinary management by a team of specialists is essential.

1. What is Sanjad-Sakati syndrome?

Sanjad-Sakati syndrome (SSS), also known as congenital hypoparathyroidism, growth retardation, and dysmorphism syndrome (HRD syndrome), is an autosomal recessive disorder. It is classified under OMIM #241410.

The first case was reported by Sanjad et al. in Saudi Arabia in 1988, and a series of 12 cases was published in 1991. The causative gene is TBCE, located on the long arm of chromosome 1 at 1q42-43, with a 12-base pair deletion (c.155-166del12) being the most common mutation ²⁾.

It primarily affects individuals of Arabian Peninsula descent and is more common in offspring of consanguineous marriages. The incidence in Kuwait is 7–18 per 100,000 births ³⁾, and in Saudi Arabia it is estimated at 1 in 40,000–100,000 births ⁵⁾. In some Middle Eastern populations, it is reported as 1 in 5,000 births. Cases have also been reported from non-Arab countries (Belgium, India) as well as Morocco, Egypt, Tunisia, Jordan, Oman, and Qatar ²⁾⁵⁾. Over 56 cases have been documented in the literature ⁵⁾.

Q In which regions is Sanjad-Sakati syndrome more common?

A

This condition is most common in populations with genetic roots in the Arabian Peninsula, with relatively high frequency in Saudi Arabia and Kuwait. The custom of consanguineous marriage is considered a contributing factor to its high frequency. However, reports from non-Arab countries such as Belgium and India also exist, indicating that it can occur in non-Arab populations as well.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Hypocalcemic seizures: Onset within the first few weeks of life. Often discovered as afebrile generalized tonic-clonic seizures²⁾
• Growth retardation: Significant decrease in both weight and height. Begins with intrauterine growth restriction
• Recurrent infections: Increased susceptibility to infections due to functional asplenia

Clinical Findings (Findings Confirmed by Physician Examination)

Systemic Findings

• Craniofacial malformations: microcephaly, deep-set eyes, hooked nose, depressed nasal bridge, long philtrum, thin lips, micrognathia, thick and large drooping earlobes
• Oral findings: enamel hypoplasia, hypodontia, microdontia, abnormal tooth morphology⁵⁾⁶⁾
• Body habitus: extreme short stature and low body weight. Reports exist of weight 5.80 kg (SD -23.05) and height 69.00 cm (SD -13.11) at age 6¹⁾
• Endocrine abnormalities: hypocalcemia and hyperphosphatemia due to PTH deficiency/hypoparathyroidism. Low IGF-1²⁾, hypothyroidism (prevalence 36%)²⁾

Ophthalmic Findings

Anterior Segment Findings

Microphthalmos/Microcornea: The most frequent ocular finding. Reported in 34 patients (52 eyes). In a series of 17 patients by Al Dhoyan et al., all had bilateral microcornea (horizontal corneal diameter 7.5–10.5 mm). Axial length was 15.93–17.8 mm (ages 4–10 years).

Corneal Lesions: Band keratopathy, corneal pannus, corneal stromal edema, and other corneal opacities (16 patients, 20 eyes). Overcorrection of hypocalcemia may contribute to band keratopathy.

Cataract: Reported in 6 patients. Cataract surgery associated with microphthalmos is often difficult due to zonular deficiency and poor pupillary dilation.

Posterior Segment and Others

Retinal vascular tortuosity: 21 patients, 42 eyes. In the series of 17 patients by Al Dhoyan et al., it was observed bilaterally in all patients.

Optic nerve lesions: Optic disc swelling, optic atrophy, unclassified optic nerve abnormalities (12 patients, 7 eyes). Buried optic disc drusen have also been suggested as a possibility.

Strabismus: Reported in 23 patients.

Others: Nystagmus (5 patients), retinal detachment (4 patients, 1 eye), retinopathy (3 patients), childhood glaucoma (1 patient, 2 eyes), persistent fetal vasculature (1 patient, 1 eye).

Q How well is vision preserved in patients with Sanjad-Sakati syndrome?

A

In the series of 17 patients by Al Dhoyan et al., all showed normal fixation. On the other hand, in cases with band keratopathy, visual acuity was reported as 20/100 to 20/125, and in severe corneal opacity cases, poor fixation was noted, indicating that visual acuity varies greatly depending on the presence of complications. Regular ophthalmologic evaluation is important.

3. Causes and Risk Factors

The causative gene for Sanjad-Sakati syndrome is TBCE (tubulin-specific chaperone E), located on the long arm of chromosome 1 at 1q42-43. The TBCE protein is a chaperone required for proper folding of α-tubulin and formation of α/β-tubulin heterodimers.

The most frequent mutation is a 12-base pair deletion in exon 3 (c.155-166del12)²⁾⁶⁾. It is considered a founder mutation common in Arab populations, and it has been suggested that the mutation may have spread to Tunisia during the conquest of North Africa by the Banu Hilal in the 7th century⁶⁾.

Microtubules are components of cilia, flagella, mitotic spindles, and are present in almost all cells of the body. Microtubule assembly defects broadly impair embryonic development, explaining the multi-organ phenotype²⁾.

Consanguineous marriage is a major factor in the high frequency of this disease in Arab populations⁵⁾⁶⁾.

Genetic Counseling

• Sanjad-Sakati syndrome is an autosomal recessive disorder; if both parents are carriers, the probability of a child being affected is 25%.
• Genetic counseling is especially important for families with consanguineous marriage.
• Prevention options include preimplantation genetic diagnosis.

4. Diagnosis and Testing Methods

Clinical Diagnosis

Clinically suspected based on the combination of characteristic facial dysmorphism, congenital hypoparathyroidism (low Ca, high P, low/deficient PTH), intrauterine growth restriction, and developmental delay.

Laboratory Findings

• Blood tests: Hypocalcemia, hyperphosphatemia, low/deficient PTH¹⁾²⁾
• Genetic testing: Screening for a 12-bp deletion in the TBCE gene confirms the diagnosis
• Head CT/MRI: Confirms calcification of the basal ganglia
• CBC: Normal T cells → useful for differentiating from DiGeorge syndrome
• Endocrine evaluation: Thyroid function, IGF-1, GH stimulation test²⁾
• Ophthalmic examination: Complete evaluation including examination under anesthesia is recommended. Measurement of horizontal corneal diameter for microcornea, axial length measurement, fundus examination
• Renal ultrasound: Screening for nephrocalcinosis ⁴⁾

Differential Diagnosis

Disease	Differences from Sanjad–Sakati syndrome
DiGeorge syndrome	Associated with cardiac defects and thymic hypoplasia (T-cell immunodeficiency). These are absent in Sanjad–Sakati syndrome
Kenny-Caffey syndrome type 1	Same TBCE mutation but with osteosclerosis. Significant clinical overlap.
Kenny-Caffey syndrome type 2	Autosomal dominant, normal intelligence, macrocephaly
Familial hypoparathyroidism	Absence of characteristic facial dysmorphism of Sanjad-Sakati syndrome
Barakat syndrome	Renal abnormalities and sensorineural hearing loss 2)

Q How to distinguish Sanjad-Sakati syndrome from Kenny-Caffey syndrome?

A

Both diseases are caused by the same TBCE gene mutation and have significant clinical overlap. Kenny-Caffey syndrome type 1 is distinguished by the presence of osteosclerosis (narrowing of the long bone medullary cavity), but accurate differentiation requires genetic testing and imaging. KCS type 2 is autosomal dominant, presents with normal intelligence and macrocephaly, and differs from Sanjad-Sakati syndrome in inheritance pattern.

5. Standard treatment

Multidisciplinary management by a team including genetics, endocrinology, and ophthalmology is essential.

Treatment of Hypoparathyroidism

Treatment	Details
Acute phase	Rapid correction with intravenous calcium (if Ca <1.80 mmol/L) 2)
Maintenance therapy	Oral calcium + active vitamin D (alfacalcidol/calcitriol) 1)
Refractory cases	Teriparatide (PTH 1-34) subcutaneous injection (1-2 times daily) 1)
Further refractory cases	Continuous subcutaneous PTH pump infusion (dose reduction of 62% possible) 1)

Other systemic management

• Infection control: prophylactic antibiotics (amoxicillin), pneumococcal vaccine ²⁾
• Hypothyroidism: treated with levothyroxine²⁾
• Growth hormone deficiency: GH therapy is generally ineffective in patients with Sanjad-Sakati syndrome²⁾
• Genetic counseling: prevention through carrier diagnosis and preimplantation genetic diagnosis

Ophthalmic management

• EDTA chelation therapy for band keratopathy
• Cataract surgery associated with microphthalmia may be difficult due to zonular deficiency and poor pupillary dilation
• Individual treatment for strabismus, cataracts, glaucoma, and retinal detachment

Precautions for calcium supplementation

High-dose calcium and vitamin D supplementation carries risks of hypercalciuria, nephrocalcinosis, and kidney stones. A report describes a case of staghorn calcium phosphate stones in an 11-year-old girl due to overcorrection of hypocalcemia ⁴⁾. Regular renal ultrasound monitoring is necessary.

Q What complications should be noted in the treatment of hypocalcemia?

A

High-dose calcium and vitamin D supplementation can cause hypercalciuria, leading to nephrocalcinosis and kidney stones. Regular renal ultrasound monitoring is necessary. Continuous subcutaneous PTH pump infusion can reduce the required doses of calcium and vitamin D, potentially lowering the risk of renal complications.

6. Pathophysiology and detailed pathogenesis

The TBCE gene is located on the long arm of chromosome 1 at 1q42-43 and encodes tubulin-specific chaperone E (TBCE). The TBCE protein assists in the folding of α-tubulin and forms α/β-tubulin heterodimers.

A 12-bp deletion (c.155-166del12, exon 3) is the most common mutation⁶⁾, and loss of TBCE function leads to impaired microtubule assembly²⁾.

Effects on Each Organ

• Parathyroid glands: TBCE and microtubules play an important role in the development of the parathyroid glands, leading to hypoparathyroidism²⁾
• Thyroid gland: Microtubules are also essential for thyroid epithelial morphogenesis (Yap & Manley 2001), resulting in hypothyroidism²⁾
• Bones and cartilage: Maturation of chondrocytes is also affected, leading to impaired growth of long bones²⁾
• Pituitary gland: Reports of pituitary hypoplasia and corpus callosum hypoplasia exist, which serve as mechanisms for pituitary hormone deficiency ²⁾
• Eyeball: Developmental disorders due to microtubule assembly failure are presumed to cause ophthalmic abnormalities including microphthalmia

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7. Latest Research and Future Prospects (Research-stage Reports)

For Patients: Please Read Carefully

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Continuous subcutaneous PTH pump infusion

Bali & Al Khalifah (2024) reported that continuous subcutaneous PTH pump infusion was used for refractory hypocalcemia in a newborn with Sanjad-Sakati syndrome, reducing calcium and vitamin D requirements by more than 50% and facilitating discharge ¹⁾. However, caution is needed for iatrogenic hypercalcemia.

In a randomized crossover trial by Winer et al. (ages 7–20 years), pump administration reduced the daily PTH dose by 62% compared to injections (pump 0.32±0.04 mcg/kg/day vs injection 0.85±0.11 mcg/kg/day), with less fluctuation in serum and urinary calcium ¹⁾.

Linglart et al. performed continuous subcutaneous PTH infusion in three children with severe hypoparathyroidism, maintaining normal calcium for 3 years with starting doses of 1–2.6 mcg/kg/day and maintenance doses of 0.1–0.5 mcg/kg/day ¹⁾.

rhPTH 1-84 (full-length PTH)

rhPTH 1-84 is FDA-approved for chronic hypoparathyroidism in adults, and promising results have been reported for use in children ¹⁾. However, chronic use of teriparatide in children is not yet approved ²⁾.

Other

• Oral potassium phosphate administration: Reported as a countermeasure for hypophosphatemia during infection in patients with Sanjad-Sakati syndrome³⁾
• Preimplantation genetic diagnosis: Possibility of carrier detection and prevention is being investigated²⁾

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8. References

1. Bali I, Al Khalifah R. Recombinant PTH infusion in a child with Sanjad-Sakati syndrome refractory to conventional therapy. JCEM Case Rep. 2024;2:luae059.
2. Benchaib NE, Elouali A, Sara A, et al. Sanjad-Sakati syndrome revealed by hypocalcemic convulsions. Cureus. 2024;16(8):e66429.
3. Sabti MA, Shamsaldeen YA. Correcting hypophosphataemia in a paediatric patient with Sanjad-Sakati syndrome through a single oral dose of potassium phosphate intravenous solution. SAGE Open Med Case Rep. 2021;9:2050313X20988412.
4. Alomar MA, Alghafees MA, Seyam RM, et al. A staghorn calcium phosphate stone in a child with Sanjad-Sakati syndrome: an iatrogenic manifestation? Cureus. 2022;14(3):e23032.
5. Alghamdi S. Oral facial manifestations of Sanjad-Sakati syndrome: a literature review. Children (Basel). 2022;9(4):448.
6. Chouchene F, Ben Haj Khalifa A, Masmoudi F, et al. Dental management of a Tunisian child with Sanjad-Sakati syndrome. Case Rep Dent. 2022;2022:9585460.