Short rib thoracic dysplasia without polydactyly due to novel variant in IFT172 gene.

Immediate identification of the cause of neonatal respiratory distress is critical as treatment is disease-specific and untreated disease may result in cardiorespiratory failure and death. We report a 3-month-old male infant, born of nonconsanguineous marriage presenting with progressively increasing breathlessness (without cough or cyanosis), fever, sweating over the forehead, feeding difficulty, poor weight gain, and developmental delay. Symptoms required hospitalizations thrice elsewhere since day 4 of life. Recovery was partial on treatment with supplemental oxygen, intravenous antibiotics and oseltamivir, and mechanical ventilation during one hospitalization. On examination, the febrile infant was drowsy with pulse rate of 120/min, respiratory rate of 56/min, and subcostal and intercostal retractions. There were pallor, periorbital edema, pedal edema, hypertension, and central cyanosis resolving with oxygen. His weight was 4.7 kg (Z score between -2 and -3, WHO growth standard), length was 59 cm (Z score between -1 and -2, WHO growth chart) with upper segment to lower segment ratio of 1.9, and head circumference was 42.3 cm (between +1 and +2 SD, WHO growth chart). He had narrow thorax, rhizomelic limb shortening [Figure 1], bilateral kidney enlargement, and generalized hypotonia. Fundus examination was normal. Occasional few crepitations were heard all over the lung fields.

Figure 1

Clinical photograph showing narrow, bell-shaped thorax and limb shortening

Except for hypercapnia and respiratory alkalosis (pH 7.45, PO2 127, PCO2 50, bicarbonate 34.8), other hematological and biochemical investigations were normal. Urine examination showed 15–20 leukocytes/hpf and 40–50 red blood cells/hpf, urine culture was sterile, and chest radiograph showed right apical lobe consolidation. Skeletal abnormalities are presented in Figure 2. Abdominal ultrasonography and CT scan showed bilaterally enlarged kidneys with hyperechoic cortex, multiple echogenic foci in the medulla (a typical sonographic abnormality of polycystic kidneys),[1] and mild hydronephrosis and hydroureter of left kidney. A small ostium secundum atrial septal defect (ASD) without pulmonary hypertension had been detected by two-dimensional echocardiography and color Doppler (day 12 of life). Repeat evaluation now additionally revealed pulmonary hypertension and tiny patent ductus arteriosus (PDA). MRI brain showed T2 hyperintense signal in posterior limb of internal capsule (suggesting delayed myelination) and simplification of gyral pattern. Clinical features (neonatal onset respiratory distress, narrow chest, rhizomelia, hypertension, and polycystic kidneys) suggested a diagnosis of skeletal ciliopathies like short rib thoracic dysplasia (SRTD).[2]

Figure 2

(a) Radiograph of chest and abdomen showing bell-shaped narrow thorax, short and horizontal ribs with irregular anterior ends; trident appearance of pelvis (arrow) with flattening of acetabular roof and a small sciatic notch and lower metaphysis of right humerus showing lateral spikes. (b) Radiograph of left wrist. Note the metaphyseal irregularities involving metacarpals and phalanges and cone-shaped phalangeal epiphysis (arrow). (c) Contrast-enhanced CT scan of the abdomen showing enlarged kidney bilaterally

The infant was treated with supplemental oxygen, oral nifedipine and sildenafil, and intravenous colistin, ceftriaxone, and metronidazole for 8 days. Fever recurred on day 8 of admission. Repeat blood culture revealed methicillin-resistant Staphylococcus aureus requiring treatment with intravenous linezolid for 14 days according to culture sensitivity. The child was discharged after 33 days on supplemental nasal oxygen. Exome testing revealed missense variants c.217G>C (p. Ala73Pro) and c.4607T>C (p. Leu1536Pro) in exon 3 and exon 42 of IFT172 gene, respectively (transcript NM_015662.1), corroborating clinical diagnosis of short rib thoracic dysplasia with or without polydactyly (OMIM 615630). IFT172gene codes for a component of the multimeric interflagellar transport (IFT) protein complex B required for anterograde transport of molecules along the cilium.[2] The c.4607T>C variant was recently reported in two patients with nephronophthisis-related ciliopathy with thoracic dystrophy and chronic respiratory distress requiring periodic mechanical ventilation.[3] The second c.217G>C variant is novel.[4] Limitation of genetic testing was the inability to test parents to confirm that variants were in trans (rather than cis) configuration.

In the absence of antenatal or perinatal risk factors, respiratory distress of neonatal onset with hypoxia in our child indicated a congenital defect. Nature of symptoms and rapid development of pulmonary hypertension over a period of 3 months were disproportionately severe for a small ASD and tiny PDA. Several clinical practices could have facilitated early diagnosis of SRTD: recording birth length, maintaining up to date anthropometry charts at every hospitalization, and measuring blood pressure routinely during hospitalizations. Finally, it is essential to be observant to detect multiorgan manifestations and synthesize a unifying diagnosis. Molecular testing establishes the diagnosis of skeletal ciliopathies (defects in biosynthesis and/or function of primary cilia) having overlapping clinical phenotypes as 23 causative genes are known.[2] For the patient, correct diagnosis results in appropriate therapy, avoiding unnecessary use of antibiotics, and preventing or monitoring for complications. For the family, unnecessary expenses are curtailed and genetic counseling is facilitated. Our family received genetic counseling to explain disease prognosis, recurrence risk of 25% for an autosomal recessive condition, and future reproductive options by first-trimester prenatal diagnosis.

Declaration of patient consent

The authors certify that appropriate patient consent was obtained.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Sunil Karande is Editor of Journal of Postgraduate Medicine.