A novel immunodeficiency syndrome associated with partial trisomy 19p13
Patient 1, a 7-year-old boy was born prematurely in the 32nd week of gestation after an uneventful pregnancy (32+2 weeks, intrauterine growth retardation (IUGR), caesarean section, oligohydramnion) with 990 g body weight (<3%), 34 cm body length (<3%), and a head circumference of 26.5 cm (<3%); his APGAR score was 8/9/9; he was discharged from neonatal intensive/intermediate care at the chronological age of 8 weeks. He is the second child to non-consanguineous healthy parents of Turkish descent aged 34 years (mother) and 40 years (father). The second patient, a now 2-year-old boy, was born prematurely as the second child of a 29-year-old Austrian mother and a 35-year-old Austrian father after an uneventful (third) pregnancy at 31+1 weeks of gestational age (IUGR, caesarean section, APGAR 7/8/9, 660 g birth weight (<3%), 34 cm length (<3%), 26.5 cm head circumference (<3%)); dismissed from neonatal intensive/intermediate care at 3 months of chronological age (corrected gestational age: 42+6 weeks). Growth parameters, weight and head circumference of both patients have remained below the third centile, recent measurements are presented in . The parents and siblings of both patients are healthy, and the extended family histories are negative for syndromic disorders or immunodeficiency.\nUpon birth, both patients showed visible organ malformations including microcephalus, facial dysmorphism including flat nasal bridge, telecanthus, short upslanting palpebral fissures, low set ears, long philtrum, narrow lips, micrognathia (A,C), as well as urogenital malformations, a perineal hypospadia in patient 1 (B) and glandular hypospadia, horseshoe kidney, cryptorchism (), camptodactylia on both feet of toes II, III, IV and overlapping of right third/fourth toes (D) in patient 2.\nIn his 1st year of life, patient 1 suffered from a bilateral incarcerated inguinal hernia and thus had to undergo surgery. Additionally, he showed developmental hip dysplasia type IVa, which was surgically treated by Pemberton's acetabuloplasty. At the age of 5 years, hypospadia required surgery whereupon a penoscrotal fistula was detected that could not be fully corrected.\nAn extensive neurological examination in the 2nd year of life (chronological age: 18 months) showed profound neurological impairment and motor plus mental retardation. Neuropaediatric examination revealed muscular hypotonia, reduced muscle strength, brisk deep tendon reflexes, negative Babinski sign; furthermore, at 18 months the boy was unable to sit, to crawl, nor to stand free; and, without further specification, the neurological report mentions showed reduced fine motor skills and speech/language retardation., Testing of the sensory system and cerebellar function was unfeasible. Moreover, a strabismus convergens alternans of the left eye was noted at the age of 18 months. Additionally, moderate bilateral sensorineural hearing loss was detected by brainstem evoked response audiometry (summarised in ). Cranial MRI showed a hypoplastic inferior vermis and a slightly extended temporal lobe (data not shown). Furthermore, the patient suffered from EEG-verified epilepsy (habitual primarily generalised seizures, EEG pathology III°) treated with valproate, which resulted in decrease of frequency of seizures (not shown). Later neurological evaluations focused on the antiepileptic treatment, while ongoing physiotherapy and ergotherapy have been aiming to improve the psychomotor situation. Dysphagia prompted the implantation of a percutaneous endoscopic gastrostomy tube at the age of 6 years. Because of a severe osteopenia (z score: −4.6 (0.26/cm3)) resulting in a pathological fracture at the age of 6 years, he is treated with bisphosphonate intravenously (18 mg) every 3 months.\nSimilar to patient 1, patient 2 suffered from inguinal hernia leading to bilateral herniotomy at 3½ months of age. He was noted to have a persisting ductus arteriosus with marginal haemodynamic relevance. Because of delayed motor and mental development (see below), progressive failure to thrive and feeding problems, intensive physiotherapy and ergotherapy was provided, additional nasogastric tube feeding with formula diet was initiated at 8 months and percutaneous gastrostomy was performed at 20 months. Like patient 1, he is neurologically and intellectually impaired with profound psychomotor retardation and muscular hypotonia (eg, sitting and belly sliding/crawling only at 2 years of age; grabbing a spoon without ability to use it), speech delay (vocalising only syllables like ‘da’ at 2 years), pharyngeal instability, microcephalus, had neonatal seizures treated with barbiturate for 10 days and two generalised seizures in the context of suspected meningitis leading to temporal antiepileptic treatment with levetiracetam, from 18 months to 21 months of age. Denver test analysis at 2 years of age revealed social contact abilities corresponding to 15 months and motor skills corresponding to 6–9 months. Basal EEG activity was found to be mildly abnormal without focal activity, and in CNS-MRI profound atrophy with multiple diffuse white matter lesions and microcystic alterations of the basal ganglia were detected (). Additionally, patient 2 suffers from hypermetropia and divergent concomitant strabismus, largely resembling patient 1; however hearing tests were normal.\nBoth patients fulfilled the classical and revised criteria of a primary immunodeficiency disorder with frequent infections and showed laboratory signs of immune dysregulation. Starting from the age of 3 weeks after birth, patient 1 developed recurrent invasive bacterial infections including episodes of sepsis; a proven Staphylococcus capitis sepsis at the age of 1½ years was followed by a severe urosepsis at 3 years. Apart from two episodes of pneumonia, chronic relapsing productive bronchitis with laboratory signs of bacterial infections recurred more than eight times per year, requiring inpatient admittance and intravenous antibiotic treatment. Moreover, the boy suffered from recurrent urinary tract infections possibly related to the hypospadia, with microbiological evidence of extended-spectrum beta lactamase (ESBL)-positive-positive Escherichia coli infection on two instances. Considering the clinical history of repeated severe bacterial infections in this patient, laboratory investigations revealing selective antibody deficiency and decreased numbers of class-switched B cells (see below), he was started on intravenous immunoglobulin (0.4 g/kg, at monthly intervals) at 5 years of age. This resulted in a significant decrease in the occurrence of infections, especially of the upper respiratory tract and lower respiratory tract.