List of key features
Depressed nasal bridge
Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome (OMIM 241410) is a rare syndrome, which has only been described in around a hundred patients. During the newborn period, affected patients present with facial dysmorphism, severe hypocalcemic tetany and generalized convulsions. Patients have very low serum concentrations of parathyroid hormone, markedly retarded skeletal maturation and low plasma levels of insulin-like growth factor 1 (IGF-1). All reported patients of HRD syndrome of Middle Eastern descent are homozygous for a 12-bp deletion in the tubulin-specific chaperone E (TBCE) gene (604934), located on chromosome 1q42-43 (Parvari et al., 2002).
Malignancies have not been reported in HRD syndrome, maybe due to persistently low concentrations of IGF-1 in these patients. The association of elevated serum IGF-1 levels with increased risk of neoplastic growth is well established epidemiologically. Growth hormone (GH) and IGF-1 promote cell proliferation, differentiation and angiogenesis and they also inhibit apoptosis, therefore, potentially favoring tumor development. Interestingly, no cancers were reported in a cohort of 230 patients with Laron syndrome, which is characterized by an inactivating mutation within the GH receptor gene and almost completely deficient IGF-1 (Steuerman et al., 2011). We present the case of a neonate with HRD syndrome, who was diagnosed with mediastinal neuroblastoma stage 4S. We describe the clinical course of the disease and discuss a potential molecular link between the two entities.
A 2-week-old male was admitted to the pediatric emergency department due to rhythmic movements of his left hand, drooling and feeding difficulties which began one day prior to his admission. He was born to healthy, consanguineous (second degree) Bedouin parents, at 39 weeks of gestation (birth weight 2570 g, small for gestational age). He had one healthy male sibling.
Upon admission, generalized tonic-clonic convulsions were observed. Vital signs were mild tachycardia (188 per minute), and normal body temperature, blood pressure and saturation. On physical examination, the patient appeared restless and had a small dysmorphic face: deep-set eyes, depressed nasal bridge with beaked nose and micrognathia. The anterior fontanel was not bulging. He had a weak Moro reflex and poor suck. Unfortunately, the parents would not allow publication of facial photographs. Laboratory tests revealed serum glucose level of 188 mg/dL. Complete blood count was remarkable for leukocytosis of 21 × 103 WBC/mm3 (38% neutrophils and 43% lymphocytes). Blood chemistry analysis revealed hypocalcemia (7.2 mg/dL, normal range 8.4–10.2 mg/dL) with low ionized calcium (0.83 mmol/L, normal range 1.1–1.35 mmol/L), hyperphosphatemia of 10.4 mg/dL (normal range 2.5–5.0 mg/dL) and mild hypomagnesemia of 1.3 mg/dL (normal range 1.7–2.2 mg/dL). No other electrolyte disturbances were found. Blood lactate level was elevated (6.8 mmol/L). Liver and renal function tests were normal. Electrocardiogram demonstrated sinus tachycardia. Chest radiograph revealed a large mass in the posterior mediastinum (Fig. 1a, b). The patient was treated by IV calcium gluconate 50 mg/kg, which successfully stopped his convulsions.
His dysmorphic facial features such as deep-set eyes, beaked nose and micrognathia, together with hypocalcemia, hyperphosphatemia (indicative of hypoparathyroidism), convulsions and parental consanguinity lead us to suspect HRD syndrome. He was found to be homozygous for a 12-base-pair deletion (155–166 del) in the TBCE gene on chromosome 1q42-43. Continuing treatment included oral therapy with calcium gluconate, vitamin D and preventive antibiotic treatment with amoxicillin.
The patient underwent a diagnostic work-up for the mediastinal mass that included: blood smear, complete and differential blood count, serum lactate dehydrogenase and uric acid. No blast cells were found in the blood smear, and serum lactate and uric acid concentrations were within normal limits. Chest computer tomography (CT) demonstrated a posterior calcified mediastinal mass, without secondary pulmonary involvement. Magnetic resonance imaging demonstrated its extension into intervertebral foramina and widening of the foramina without vertebral body invasion (Fig. 2). Biopsy of the mass was performed. Histological assessment and immune-histochemical findings were consistent with neuroblastoma, poorly differentiated type, with multiple calcifications. Ki67 (proliferation marker) expression was observed in about 50% of tumor cells. Bone marrow biopsy and abdominal CT ruled out invasion into bone marrow or liver. Meta-iodobenzylguanidine scan was normal, without evidence of other organ involvement. N-myc expression was negative. Cumulatively, given these findings, the patient was diagnosed with Stage 4S neuroblastoma. Because of the patient’s age and localization of the tumor, no surgical excision or chemotherapy was necessary, and the mass markedly regressed until complete recovery by the 18-month follow-up period.
We present here a case of a two-week-old infant, homozygous for a 12-base-pair deletion (155–166 del) in the TBCE gene, diagnosed with HRD syndrome together with mediastinal congenital stage 4S neuroblastoma.
According to the International Neuroblastoma Staging System, neuroblastoma stage 4S is a specific stage of localized primary tumor, with metastases restricted to the liver, skin or bone marrow (<10% of bone marrow), in infants less than 1 year of age. This tumor, which comprises 5% of all neuroblastoma patients, has paradoxically favorable prognosis with 2-year survival rates ranging from 75 to 90%. Most stage 4S patients do not require chemotherapy treatment, as a result of spontaneous tumor regression (Evans et al., 1981).
To the best of our knowledge, this is the first description of malignancy in a patient with HRD syndrome, especially a congenital one. To this end, the role of TBCE protein in tumor development is of particular interest for us. The TBCE gene encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Mutations in the TBCE gene lead to a reduction in the amount of available tubulin to be incorporated into microtubules, causing severe cytoskeletal defects, such as those described in patients with HRD syndrome. Fibroblasts and lymphoblastoid cells in HRD patients have lower microtubule density at the microtubule-organizing center in diseased cells (Parvari et al., 2002). Microtubules are of critical importance for cell development and function. Indeed, recent evidence demonstrates that mutation in the TBCE gene results in the disturbance of microtubules in auditory nerve and in cochlear cell degeneration, presumably resulting from enhanced apoptosis (Rak et al., 2013). Cumulatively, these observations support the possibility of enhanced apoptosis of neuroblastoma cells in our patient due to dysfunctional microtubules. The role of apoptosis in spontaneous regression of neuroblastoma is well established (Brodeur, 2018).
In conclusion, we described the first reported case of malignancy in a patient with HRD syndrome. We attribute lack of other reports of neoplasia in HRD patients to the rarity of this syndrome and to the fact that the patients have a diminished life expectancy. Additionally, low GH and IGF-1 serum levels previously reported in this unique syndrome may be protective against neoplasia.
Conflicts of interest
There are no conflicts of interest.
Brodeur GM. Spontaneous regression of neuroblastoma. Cell Tissue Res. 2018; 372:277–286
Evans AE, Baum E, Chard R. Do infants with stage IV-S neuroblastoma need treatment?. Arch Dis Child. 1981; 56:271–274
Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loeys B, Zecic A, et al.; HRD/Autosomal Recessive Kenny-Caffey Syndrome Consortium. Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive kenny-caffey syndrome. Nat Genet. 2002; 32:448–452
Rak K, Frenz S, Radeloff A, Groh J, Jablonka S, Martini R, et al. Mutation of the TBCE gene causes disturbance of microtubules in the auditory nerve and cochlear outer hair cell degeneration accompanied by progressive hearing loss in the pmn/pmn mouse. Exp Neurol. 2013; 250:333–340
Steuerman R, Shevah O, Laron Z. Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol. 2011; 164:485–489