The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 4817-4820
Copyright © 2004 by The Endocrine Society
A Case of Chromosome 22q11 Deletion Syndrome Diagnosed in a 32-Year-Old Man with Hypoparathyroidism
Naim M. Maalouf,
Khashayar Sakhaee and
Clarita V. Odvina
Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8885
Address all correspondence and requests for reprints to: Dr. Clarita V. Odvina, Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8885. E-mail: clarita.odvina{at}utsouthwestern.edu.
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Abstract
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Congenital hypoparathyroidism typically manifests with hypocalcemia with or without associated characteristic physical findings and is usually diagnosed during the neonatal period. This report describes an African-American male who was diagnosed at age 32 yr to have dysgenesis of the parathyroid glands due to chromosome 22 microdeletion. Symptomatic hypocalcemia did not develop until age 14 yr, a few weeks after initiation of anticonvulsant therapy for generalized tonic-clonic seizures. Because of the timing for onset of symptomatic hypocalcemia, it was presumed that the patient had anticonvulsant-induced hypocalcemia, and he carried that diagnosis for 18 yr. Chromosome 22q11 deletion syndrome was first suspected at age 32 yr, based on the findings of subtle dysmorphic facial features and a history of learning disability in a patient with PTH-deficient hypocalcemia. The diagnosis was confirmed by fluorescence in situ hybridization analysis.
This case underscores the variable clinical presentation of this congenital form of hypoparathyroidism. Chromosome 22q11 microdeletions are relatively common, and the diagnosis should be considered even in adults with hypoparathyroidism because of the potential benefit of genetic counseling.
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Introduction
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HYPOPARATHYROIDISM (HP) IS a clinical disorder with diverse etiologies (1). In adults, the majority of cases of HP are due to acquired conditions, such as an autoimmune process or an injury to the parathyroid glands during neck surgery (1, 2). Genetic mutations, which could result in defective synthesis of PTH, peripheral resistance to the effects of PTH, or abnormal development of the parathyroid glands, usually manifest clinically in childhood (3). Agenesis or dysgenesis of the parathyroid glands can occur alone but is more commonly associated with other developmental abnormalities, such as thymic hypoplasia, defects in the cardiac outflow tract, and facial dysmorphism (2, 3). Moreover, it is rarely diagnosed in adulthood.
We hereby present the case of a PTH-deficient patient with distinct facial features, in whom deletion on chromosome 22q11 was identified during adulthood using fluorescence in situ hybridization (FISH) analysis. As in this patient, the diagnosis of chromosome 22q11 deletion syndrome can be easily overlooked because the onset of hypocalcemia may appear after childhood and due to the variable phenotype. This case report and a review of the relevant literature hope to call attention to this syndrome as a potential cause of HP outside the neonatal period.
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Case Report
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The institutional review board waived the need for review and approval of this case report by the board. A 32-yr-old African-American man was referred to our clinic for the management of hypocalcemia. His past medical history was significant for learning disability and short stature. He developed seizures at 14 yr of age. At the time of presentation, serum calcium concentration was 7.3 mg/dl (1.82 mmol/liter). In his medical records, there was no indication that serum calcium concentration was ever measured before the onset of seizure. In addition, there was no reference to any plans to determine the cause of his hypocalcemia. For his seizures, he was treated initially with phenytoin and later switched to phenobarbital. A few weeks after initiation of the anticonvulsant therapy, he presented with symptomatic hypocalcemia (leg cramps and perioral tingling). His serum calcium concentration at the time was 5.4 mg/dl (1.35 mmol/liter). Hypocalcemia was attributed to the hypocalcemic effect of the antiseizure medications, and he was started on calcium and vitamin D. He remained asymptomatic for 18 yr until he discontinued his medications and subsequently presented with hypocalcemia and seizures.
At the time of his clinic visit, physical examination revealed a thin man who was noted to have a hypernasal speech. He weighed 55 kg and his height was 168 cm. He had a prominent forehead, sparse, thin eyebrows and eyelashes, and hypertelorism (Fig. 1
). Funduscopic examination did not reveal any evidence of cataract. His nasal bridge was flat and he had a high-arched palate. Cardiac examination was significant for a loud second component of S2. Chest and abdominal examination findings were unremarkable. Chvostek’s sign was positive. He did not have brachydactyly or dysmorphic nails.
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FIG. 1. Close-up photograph of the patient, showing the prominent forehead, small eyes, hypertelorism, and sparse, thin eyebrows and eyelashes.
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Laboratory data were obtained while the patient was off all medications. Serum total calcium concentration was low at 7.0 mg/dl (1.75 mmol/liter), and serum albumin concentration was 4.0 g/dl (40 g/liter). Serum phosphorous concentration was slightly elevated at 4.7 mg/dl (1.52 mmol/liter), and serum magnesium concentration was normal at 1.4 mEq/liter (0.70 mmol/liter). Serum PTH concentration was inappropriately low at 11 pg/ml (11 ng/liter) and serum 1,25-dihydroxyvitamin D concentration was below the lower limit of detection of the assay, at less than 10 pg/ml (<26 pmol/liter). Twenty-four-hour urinary calcium excretion was low at 11 mg per 24 h (0.275 mmol/d), and creatinine clearance rate was normal at 124 ml/min.
Based on the above findings, the possibility of chromosome 22q11 deletion syndrome was suspected. Standard chromosome analysis showed a normal male karyotype. FISH analysis was performed to screen for possible chromosomal deletion in the region specific for the DiGeorge syndrome (TUPLE1, D22S553, D22S609, D22S942) (Vysis, Inc., Downers Grove, IL) (4). This revealed a submicroscopic deletion in the DiGeorge/velocardiofacial syndrome critical region on chromosome 22. Magnetic resonance imaging of the brain was normal, with no intracranial calcification. Because of the cardiac findings, a transthoracic echocardiogram was performed, which showed normal cardiac chambers and normal outflow tracts.
The patient was started on 400 mg (20 mmol) elemental calcium as calcium citrate salt, orally twice daily and treatment with calcitriol 0.25 µg orally twice daily. Valproic acid (500 mg orally twice daily) was restarted to control the seizures. Repeat laboratory evaluation showed a rise in total serum calcium concentration to 8.4 mg/dl (2.10 mmol/liter) and normalization of the serum phosphorus concentration at 4.0 mg/dl (1.29 mmol/liter).
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Discussion
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Although the most common cause of hypoparathyroidism in adults is surgical excision of or damage to the parathyroid glands during neck surgery, other causes should also be considered (1, 2). For instance, HP can result from destruction of the parathyroid glands due to an autoimmune process, and patients can present with HP alone or in association with other endocrine deficiency states. Furthermore, congenital abnormalities can result in failure of the parathyroid glands to develop. HP due to congenital agenesis or hypoplasia of the parathyroid glands typically presents early in life (3) and is rarely considered in adult patients. This report describes a male patient with PTH-deficient HP due to chromosome 22q11 deletion syndrome, a congenital condition that results in parathyroid gland hypoplasia and is usually diagnosed in early childhood (5, 6). In addition to the biochemical findings, certain features such as subtle dysmorphic facial anomalies, short stature, and learning disability raised our suspicion for this diagnosis. These findings were overlooked for many years, and failure to identify the condition earlier may have been partly due to the absence of symptomatic hypocalcemia before the initiation of anticonvulsant therapy. The diagnosis was established by FISH analysis, which disclosed the presence of a microdeletion in the region of chromosome 22q11.
This syndrome was first described in 1965 in young children with the triad of hypoparathyroidism, thymic hypoplasia, and recurrent infections and was initially termed the DiGeorge syndrome (7). Microdeletion in region 22q11 of one copy of chromosome 22 is found in the majority of cases (4). As a consequence of the microdeletion, there is congenital failure in the development of the derivatives of various pharyngeal arches and pouches. The chromosome 22q11 region has been entirely sequenced; however, no single gene has yet been proven to play a definite role in the pathogenesis of the syndrome (5). Two other separately described disorders, velocardiofacial syndrome (8) and conotruncal anomalies face syndrome (9), were also found to be associated with deletions at 22q11. As a result, these two syndromes have now been combined with the DiGeorge syndrome into one genetic entity, known as chromosome 22q11 deletion syndrome. Deletion of this critical region is estimated to affect approximately 1/7500 live births (10), and the syndrome is the most common contiguous gene deletion syndrome in humans. This microdeletion typically occurs de novo, although it is inherited in about 10–20% of cases (11). Thus, individuals with a 22q11 deletion have a 50% risk of having an affected offspring with each pregnancy. FISH-based assays to detect the deletion are now commercially available to confirm the diagnosis of chromosome 22q11 deletion syndrome. These assays also provide couples at risk the possibility of genetic counseling and prenatal diagnostic testing and assist them with their reproductive decisions (12).
In addition to the originally described triad, a wide variety of clinical findings may accompany the chromosome 22q11 deletion syndrome (6). Most affected patients are diagnosed neonatally with congenital heart disease, hypocalcemia, and/or dysmorphic features (5, 11). On the other hand, most adult cases are identified as asymptomatic parents of affected children (13). Affected patients may have one or more clinical findings, but there seems to be no genotype-phenotype correlation, even among affected members of the same family (14) and in monozygotic twins (15). The characteristic facial features associated with this syndrome have been classically described as prominent nose with hypoplastic alae nasi, midface hypoplasia, minor auricular anomalies, and micrognathia. Many African-American patients with this syndrome were found to lack these classical findings in one study (16), and this may partly explain the delayed diagnosis in our patient.
Hypocalcemia in chromosome 22q11 deletion syndrome most frequently manifests during the neonatal period (11, 17), probably due to the interruption at birth of the active transport of calcium from the mother to the fetus and an insufficient intake of calcium in the first few days of life (18). However, a spectrum of parathyroid gland dysfunction has been described in this syndrome, ranging from hypocalcemic HP (seen in up to 60% of cases) to normocalcemia with a normal serum PTH concentration (18, 19, 20). This dysfunction may also evolve over time within the same individual (20, 21). HP as the presenting finding leading to the diagnosis of the chromosome 22q11 deletion syndrome has been reported in very few adult cases (22, 23).
An unusual characteristic in the patient in this report is the late development of hypocalcemia, i.e. during puberty. This late-onset appearance of symptomatic hypocalcemia is probably secondary to inadequate parathyroid reserve (24), in which PTH secretion may be sufficient to maintain normocalcemia under basal conditions but cannot adequately increase in response to a hypocalcemic stress. This concept was first demonstrated using an infusion of EDTA, a substance known to chelate ionized calcium. EDTA uncovered latent hypoparathyroidism in a woman suspected to have the DiGeorge syndrome, based on her strong family history of the syndrome and her personal history of tetralogy of Fallot (25). One clinical situation in which deficient PTH secretory reserve is detectable in patients with chromosome 22q11 deletion syndrome is during hypocalcemia induced by cardiopulmonary bypass surgery (26). In our patient, it was felt that the introduction of anticonvulsant therapy unmasked the latent hypoparathyroidism. Some anticonvulsants are known to alter hepatic 25-hydroxylation of vitamin D and therefore potentially cause mild hypocalcemia (27, 28). Symptomatic hypocalcemia, however, rarely develops because of the compensatory increase in PTH secretion (29), which is defective in our patient.
In conclusion, HP first diagnosed in adulthood may, in rare cases, be due to parathyroid gland hypoplasia secondary to the chromosome 22q11 deletion syndrome. The diagnosis could be missed due to either the unfamiliarity of physicians with the syndrome or the variable and sometimes subtle phenotype. Because chromosome 22q11 deletion is relatively common, the diagnosis should be considered in patients with idiopathic hypoparathyroidism because of the potential benefit that can be derived from genetic counseling.
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Footnotes
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This work was supported by National Institutes of Health Grants M01-RR00633 and T32-DK07307.
Abbreviations: FISH, Fluorescence in situ hybridization; HP, hypoparathyroidism.
Received March 3, 2004.
Accepted June 30, 2004.
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References
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Abstract
Introduction
