Genetic Disorders: Tetany in a 9-Year-Old Girl

A 9-year-old girl presented with a 3-hour history of unremitting severe cramping in her hands and legs. A similar episode occurred a month earlier, but it resolved with massage. She was taking no medications. The patient had a heart murmur; 3 years earlier, she had undergone cardiac surgery to repair a large atrial septal defect. She had been well since then.

Examination revealed an alert, oriented girl in pain from persistent cramping and flexion of her hands, wrists, and legs. Her speech was hypernasal. Her oral temperature was 37.1°C (98.8°F); heart rate, 91 beats per minute; respiratory rate, 28 breaths per minute; oxygen saturation, 99% on room air; and blood pressure, 109/54 mm Hg. She experienced carpal spasm after inflation of the blood pressure cuff on her left arm (Trousseau sign).

The patient had no history of recurrent illnesses or recurrent infections (such as otitis media). She had been able to tolerate vaccinations without adverse reactions. There was no history of psychiatric illness. She weighed 25.4 kg (25th percentile) and was 124 cm tall (3rd percentile). There were no developmental delays. However, the patient had a history of learning disabilities and reported difficulty with her school studies. At age 9 years, she was a second-grade student.

The patient had a long face with narrow palpebral fissures, tubular nose, recessed mandible, and high arched palate (Figure 1). A positive Chvostek sign (facial muscle spasm induced by tapping over the facial nerve about 2 cm anterior to the earlobe and below the zygomatic arch) was present. Her fingers were long and tapered (Figure 2).

Cardiac examination revealed a 2/6 systolic ejection murmur. A well-healed scar was present on the right side of her chest.

Neurologic examination revealed increased tone in her forearms and hands with flexion of her wrists and fingers. She was unable to straighten her fingers and had a weak handgrip. Decreased strength was also noted in her lower extremities and she had pain when walking on her heels and tiptoes. Her deep tendon reflexes were +3 in both upper and lower extremities. Sensation and function in cranial nerves II through XII were intact.

Laboratory data included white blood cell count, 4200/µL (normal, 4000 to 11,000/µL); lymphocyte count, 39.8% (normal, 22% to 69%); sodium, 147 mEq/L; potassium, 3.8 mEq/L; chloride, 106 mEq/L; bicarbonate, 23 mEq/L; urea nitrogen, 12 mg/dL; creatinine, 0.6 mg/dL; glucose, 93 mg/dL; total calcium, 6.6 mg/dL (normal, 8 to 10.5 mg/dL); phosphorus, 6 mg/dL (normal, 3.2 to 6.3 mg/dL); magnesium, 1.5 mEq/L (normal, 1.3 to 2.0 mEq/L); albumin, 4.7 g/dL per 100 mL (normal, 3.2 to 5.0 g/dL per 100 mL); and parathyroid hormone, 7 pg/mL (normal, 10 to 65 pg/mL). The ECG showed a QT corrected (QTc) interval of 0.42 (normal, less than 0.44) and normal rhythm.

CD3, CD4, and CD8 counts were not checked because the patient's white blood cell and lymphocyte counts were within normal limits and she had no history of recurrent illnesses or infections.

TO WHAT DIAGNOSIS DO THESE FINDINGS POINT?

ANSWER: VELOCARDIOFACIAL SYNDROME

In hypocalcemia, the salient clinical symptoms are neuromuscular. Our patient presented in tetany, with positive Chvostek and Trousseau signs (peripheral neurologic findings seen in hypocalcemia).^1,2 She was given an intravenous infusion of 10% calcium gluconate and was placed on continuous cardiac monitoring. Her neuromuscular symptoms resolved once her total serum calcium improved (to 7.6 mg/dL).

Other symptoms associated with acute hypocalcemia are^1,2:

• Bronchospasm.
• Laryngeal stridor.
• Dysphagia.
• Vomiting.
• Muscle weakness and/or muscle spasms.
• Distal extremity numbness and tingling.
• Irritability and confusion.
• Seizures.
• Prolongation of the QTc interval.

Normal laboratory values for magnesium, phosphorus, albumin, and renal function helped exclude key metabolic disorders that cause hypocalcemia.^1,2 A genetic cause of hypocalcemia was suspected because of the patient's history of congenital heart disease, her craniofacial features, and the absence of a clear metabolic cause.

Chromosome analysis and a fluorescence in situ hybridization (FISH) study of a probe on chromosome 22 were done. The karyotyping was conducted as part of a standard genetic workup for patients in whom a chromosomal abnormality is suspected to check for translocations or more apparent deletions (macrodeletions) in the chromosomes. Chromosome analysis showed a normal female karyotype (46,XX).

FISH analysis was also ordered to rule out a microdeletion syndrome, because only one third of interstitial chromosomal deletions are detected by standard cytogenetic analyses.^3,4 FISH uses a DNA cosmid probe tagged with a fluorescent label for a specific region within the genome. In this patient, FISH analysis showed a small deletion in the long arm (q) of chromosome 22 at band site 11.2. This deleted area represents an interstitial deletion of chromosome 22q of bands 11.21 to 11.23--a chromosomal deletion consistent with DiGeorge syndrome and velocardiofacial syndrome (VCFS).⁴

VELOCARDIOFACIAL SYNDROME

The spectrum of clinical presentations seen in patients with DiGeorge syndrome and VCFS represents phenotypic variability of a single genetic defect. In 1993, Wilson and colleagues⁵ proposed a collective acronym for genetic syndromes with the common etiology of monosomy 22q11. The acronym is CATCH 22: Cardiac defects, Abnormal facies, T-cell deficit from thymic hypoplasia, Cleft palate, and Hypocalcemia from parathyroid hypoplasia.^4-6 Both DiGeorge syndrome and VCFS fall within this spectrum. As such, the variability of clinical presentation seen in these patients is extensive: DiGeorge syndrome resides at the severe end of the spectrum (T-cell immunodeficiency, thymic and parathyroid hypoplasia, and outflow tract cardiac defects) and VCFS at the mild end.⁷ In DiGeorge syndrome, hypocalcemia and immune defects from T-cell deficiency are typically recognized in the newborn period; in VCFS, these findings are less common. VCFS is generally diagnosed at an older age in patients with craniofacial and palatal abnormalities.^3,6

Also known as Shprintzen syndrome, VCFS was characterized in 1978 by Dr Robert Shprintzen and colleagues.⁸ The syndrome involved cleft palate, cardiac anomalies, typical facies, and learning disabilities.^6,8 Today, the worldwide prevalence of VCFS is estimated to be 1 in 4000.⁴ The defining phenotype of VCFS is divided into 3 clinical areas:

• Velo-: palatal deformities, such as cleft of the secondary palate and/or velopharyngeal incompetence.
• Cardio-: congenital cardiac defects, present in 85% of patients. Ventricular septal defect (62%), right aortic arch (52%), and tetralogy of Fallot (21%) are the most common.
• Facial-: craniofacial findings, such as microcephaly (40% to 50%), narrow palpebral fissures, a prominent bulbous nose and nasal root from hypoplastic alae nasi, a long narrow face with a small mouth, and a recessed mandible with a small chin (micrognathia).^3,6

Other features include⁶:

• Postnatal growth retardation leading to short stature (in 33% of those affected).
• Hypernasal speech.
• Conductive hearing loss related to cleft palate and auricular anomalies.
• Hyperextensible hands and tapering fingers (in 63%).

In newborns, hypotonia may be present (in 70% to 80%) along with transient neonatal hypocalcemia (20%). In about 40% of older patients, delayed speech development, learning disabilities, and mild intellectual impairment are seen.³ Psychiatric illness--especially schizophrenia and bipolar spectrum disorders--is present in about 25% of patients.This high rate of psychosis suggests a genetic link between 22q and these psychiatric disorders.⁶

VCFS occurs in patients as a new mutational event about 85% of the time. In the remaining cases, monosomy 22q is inherited with an autosomal dominant Mendelian inheritance pattern. In these cases, there is a 50% chance that the deletion will be passed from one generation to the next. Parental chromosomal studies and FISH analyses are recommended for those couples with an affected child who are planning to have more children.⁶ These studies clarify potential recurrence risks for these families.

TREATMENT

Therapy to prevent recurrence of acute hypocalcemia is lifelong. This patient started a daily regimen of calcium carbonate, calcitriol, and aluminum hydroxide to maintain balanced serum levels of calcium and phosphorus. The family was given nutritional guidelines to help their child maintain a low phosphate diet. Outpatient follow-up was scheduled to monitor calcium and phosphorus serum levels and for renal ultrasonography to evaluate for nephrocalcinosis from the daily exogenous calcium load.

References:

REFERENCES:

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