Neonatal hypocalcemia and congenital heart defects has been known as the first clinical manifestation of the chromosome 22q11.2 deletion syndrome (22q11DS). However, because of its wide clinical spectrum, diagnosis of 22q11DS can be delayed in children without classic symptoms. We report the case of a girl with the history of imperforate anus but without neonatal hypocalcemia or major cardiac anomaly, who was diagnosed for 22q11DS at the age of 11 after the onset of overt hypocalcemia. She was born uneventfully from phenotypically normal Korean parents. Imperforate anus and partial cleft palate were found at birth, which were surgically repaired thereafter. There was no history of neonatal hypocalcemia, and karyotyping by GTG banding was normal. At the age of 11, hypocalcemia (serum calcium, 5.0 mg/dL) and decreased parathyroid hormone level (10.8 pg/mL) was noted when she visited our Emergency Department for fever and vomiting. The 22q11DS was suspected because of her mild mental retardation and velopharyngeal insufficiency, and a microdeletion on chromosome 22q11.2 was confirmed by fluorescence
The chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome with an estimated incidence of 1 in 4,000 live births
The extreme diversity of clinical presentations makes 22q11DS without well-known phenotype a diagnostic challenge. Because of possible underdiagnoses, true prevalence of this syndrome can be much higher than reported
An 11-year-old girl visited our Emergency Department with fever, cough, abdominal pain and vomiting. Hypocalcemia (serum calcium, 5.0 mg/dL; ionized calcium, 0.74 mM) was noted on laboratory analysis, with normal albumin (4.3 mg/dL), and upper normal limit level of phosphorus (5.6 mg/dL).
She was born with 3,040 g of body weight at 37 weeks of pregnancy at our hospital and was the second child of phenotypically normal Korean parents. Imperforate anus with rectovestibular fistula and partial cleft palate were found at birth. Atrial septal defect (ASD, 3.5-mm width) was diagnosed on echocardiography performed on the first day of life. However, the karyotyping revealed normal chromosomal pattern by GTG banding. Descending colostomy was performed on the first day of life and followed by colostomy repair at 9 months of age. Pena operation (posterior sagittal anorectoplasty) was performed at 4 months of age and transposition anoplasty was done at 7 months of age. Palatoplasty for cleft palate was performed at 14 months of age, and again at 9 years of age, velopharyngeal insufficiency was surgically corrected by superiorly based pharyngeal flap with lateral port control. Echocardiography at 20 months of age showed no intracardiac anomaly, suggesting spontaneous closure of previously observed ASD. She had suffered from frequent respiratory tract infections with otitis media and chronic constipation, but there was no history of severe systemic infection. Her developmental milestones were delayed, and she was diagnosed for mild intellectual disability at 8 years of age (Intelligence quotient 57 on Korean Wechsler intelligence scale for children). She was attending a public school without specific behavioral problems, although her academic performance was poor.
On the third day of life, her calcium (9.2 mg/dL), phosphorus (4.5 mg/dL), and ionized calcium (1.05 mM/L) levels were normal. Her calcium level was also normal on preoperative screening before surgery at 4, 7, and 9 months of age (10.5, 10.8, and 10.6 mg/dL, respectively). Her calcium level was in low normal range on laboratory studies at 20 months and 7 years of age (9.1 and 8.9 mg/dL, respectively). The parents denied any history of hypocalcemic symptoms during her infancy or childhood.
Her facial features appeared mildly dysmorphic, with hypertelorism, short philtrum and small down-turned mouth. Hypernasal speech was not observed. At the time of hypocalcemia onset at 11 years of age, her height was 141 cm (25th percentile) with weight 31 kg (10th–25th percentile). Her midparental height was 157 cm (10th–25th percentile). Her wrist X-ray showed bone age of 12 years without any evidence of rickets. Serum magnesium level was normal (1.63 mg/dL). The parathyroid hormone (PTH) level was inappropriately low (10.8 pg/mL; reference rage, 15–65 pg/mL) considering her plasma calcium level, suggesting hypocalcemia due to hypoparathyroidism. Serum 25(OH)D level was also decreased (11.4 ng/mL; reference range, 30–100 mg/mL). Her thyroid function was normal (thyroid-stimulating hormone, 0.28 uIU/mL; free T4, 1.68 pg/mL).
Intravenous calcium (calcium gluconate, 100 mg/kg) was given during the first 3 days after admission, followed by oral calcium (calcium lactate, 300 mg/kg/day). Vitamin D (calcitriol, 0.75 µg/day) treatment was started on the 2nd hospital day. She was discharged on the 6th hospital day when her calcium level was 6.5 mg/dL. Her calcium level increased to 8.3 mg/dL on follow-up visit at 1 week after discharge, and her PTH level was still low (9.0 pg/mL). Although 25(OH)D level has been normalized (25.5 and 30.5 ng/mL after 2 months and 3 months, respectively) after treatment, daily administration of calcium (calcium carbonate, 62.5 mg/kg/day) and calcitriol (0.5 µg/day) was required to maintain normocalcemia (serum calcium 9.2 and 8.3 mg/dL after 2 and 3 months, respectively).
22q11DS was suspected based on her history of velopharyngeal insufficiency and mental retardation, and fluorescence in situ hybridization analysis confirmed a deletion of chromosome 22q11.2 (
The present case suggests that the diagnosis of 22q11DS can be delayed in those without major clinical features. Our patient did not have neonatal hypocalcemia or major cardiac anomaly, although she had imperforate anus, velopharyngeal insufficiency, and delayed development, and subtle but characteristic facial features of 22q11DS
The chromosome 22q11 region is very unstable, and misalignment of chromosome-specific low-copy repeats (LCR22A-H) during nonallelic homologous recombination can lead to the deletion of the 22q11.2 region
Neonatal hypocalcemia due to hypoparathyroidism has traditionally been known as the first manifestation that has been reported in 43%–60% of patients with 22q11DS
A recent study including 138 adults with 22q11DS reported 80% of patients have a lifetime history of hypocalcaemia
Hypocalcemia is one of the unique features of proximal deletions (LCR22A-D or LCR22A-B) in patients with 22q11DS
A provocation test using sodium bicarbonate infusion was reported to be able to evaluate residual parathyroid function in normocalcemic patients with 22q11DS
Vitamin D deficiency is very common in Korean children, but calcium and PTH levels were normal in most children with vitamin D deficiency
Congenital heart defects are one of main clinical feature of 22q11DS. Although serious cardiac anomalies were present in most patients in earlier studies, the prevalence seems to be about 40% according to recent papers
A delay in the diagnosis of 22q11DS with noncardiac symptoms has been reported in a recent study including 228 patients with 22q11DS
The incidence of anorectal malformation is approximately 1 in 5,000 live births
There are several reports on the delayed diagnosis of 22q11DS, and recent cases of 22q11DS diagnosed after 10 years of age are summarized in
A correct diagnosis is important in patients with 22q11DS because of the increased risk for later-onset medical and neuropsychiatric problems, including schizophrenia (>20-fold increase), anxiety disorder, epilepsy, and Parkinson disorder
Our case suggest that imperforate anus, without major cardiac anomaly, can be a clinical presentation of 22q11DS, and that 22q11DS should be considered in the differential diagnosis of hypocalcemia in any age because of its wide clinical spectrum. Furthermore, patients with 22q11DS should be informed of the symptoms of hypocalcemia that may develop later, and periodic screening for serum calcium level should be considered.
Variable | Botto et al. | Cancrini et al. | Lee et al. | Fomin et al. | Hiéronimus et al. | Friedman et al. | Bassett et al. |
---|---|---|---|---|---|---|---|
Published year | 2003 | 2014 | 2004 | 2010 | 2006 | 2016 | 2015 |
Country | USA | Italia | Korea | Brazil | France | Israel | Canada |
Sex, male:female | 43 (21:22) | 228 (112:116) | 43 (19:24) | 14 (8:6) | 19 (11:8) | 8 (3:5) | 78 (36:42) |
Age (yr), mean±SD (range) | Infancy | Mean 2 (0–36) | 5.3±4.2 (2–23) | Mean 8 (0–18) | Median 18 (0–48) | >10 (10–57) | 31.5±10.5 |
Hypocalcemia | 21% | N/A | 47% | 36% | 38% | 38% | 64% |
Neonatal hypocalcemia | N/A | 43% | N/A | N/A | 19% | N/A | 14% |
Hypoparathyroidism | N/A | 19% | 16% | 29% | 50% | 25% | N/A |
Cardiac anormalies | 81% | 79% | 84% | 86% | 58% | 50% | 25.8% |
Gastrointestinal anomalies | 3% | 6% | 2.3% | - | - | - | N/A |
Renal anomalies | 2.3% | N/A | - | - | - | - | 6% |
Velopharyngeal insufficiency | 14% | 31% | N/A | N/A | 26% | 13% | 42%a) |
Cleft palate | 12% | 10% | 19% | N/A | 16% | 13% | 31%b) |
Intellectual disability | N/A | 70% | N/A | N/A | 84% | N/A | 92.3% |
Developmental delay | N/A | 48% | N/A | N/A | N/A | 75% | N/A |
Behavior abnormalities | N/A | 7% | N/A | N/A | 50% | 50% | N/A |
Psychiatric disorders | N/A | 5% | N/A | N/A | 10% | 13% | 58%c) |
(Recurrent) Infections | N/A | 56% | N/A | 50% | 32% | 25% | 39%d) |
Thymic aplasia | 28% | 28% | 16% | N/A | 10% | N/A | N/A |
Thyroid disease | - | 2% | 7.6% | 7.1% | - | - | 26% |
Dysmorphic face | 80% | 100% | N/A | 79% | 100% | 88% | 100% |
SD, standard deviation; N/A, not available.
a)Those with submucosal cleft palate and/or velopharyngeal insufficiency. b)Those with surgically repaired palatal anomalies. c)Including schizophrenia, major depression, anxiety disorder, impulse control disorder, and substance use disorder (23% if schizophrenia ascertainment subgroup only). d)Recurrent pneumonia.
Study | Age | Sex | Cause of diagnosis | Ca level (mg/dL) | Neonatal hypocalcemia | Dysmorphic face | Cardiac abnormality | Neuropsychiatric problems | Other associated abnormality |
---|---|---|---|---|---|---|---|---|---|
Maalouf et al. | 32 | M | Hypocalcemia, seizure | 7.0 | Unknown | + | None | Learning difficulty | - |
Johnston et al. | 29 | F | Symptomatic hypocalcemia | 6.56 | Transient | + | None | Learning difficulty | Velopharyngeal insufficiency |
Özkale et al. | 13 | M | Hypocalcemic seizure | 5.8 | Permanent | + | none | Autism, MR | - |
12 | F | Seizure | normal | Unknown | + | ASD | Mild MR | Recurrent respiratory infection | |
Hyun et al. | 12 | M | hypocalcemic seizure | 6.5 | Unknown | + | Rt aortic arch | Learning difficulty mild MR | Cleft palate, decreased T cell number |
12 | M | Hypocalcemic seizure | 6.9 | Unknown | + | PDA | Learning difficulty | - | |
Nakada et al. | 36 | F | Clouding of consciousness | 8.3 | Unknown | + | TOF | Learning difficulty | Decreased CD 8 T cell, Hashimoto' thyroiditis |
Kambo et al. | 17 | M | Hypocalcemic seizure | 6.64 | Unknown | + | Mild cardiac abnomality | MR | Cleft palate, parathyroid hypoplasia |
Korpaisarn et al. | 26 | M | Carpopedal spasm, numbness, tingling | 6.0 | Unknown | + | None | Mild MR | - |
Eryilmaz et al. | 11 | M | Hypocalcemic seizure | 6.3 | Unknown | + | None | Delayed milestone | Recurrent respiratory infection |
An et al. | 13 | M | Hypocalcemic seizure | 6.7 | Unknown | + | None | Learning difficulty | Cleft palate |
Present case | 11 | F | Hypocalcemia | 5.0 | None | + | ASD | Learning difficulty | Imperforate anus, cleft palate, velopharyngeal insufficiency |
MR, mental retardation; ASD, atrial septal defect; PDA, patent ductus arteriosus, TOF, Tetralogy of Fallot.