Congenital pyloric atresia (CPA) is a rare congenital gastrointestinal tract anomaly, with obstruction at the stomach outlet (pylorus). The CPA in the neonatal period has a classical presentation of feed intolerance, non-bilious vomiting, and upper abdominal distension, with an X-ray suggestive of a classical single bubble appearance. The late presentation has been mainly seen in the form of failure to thrive. Here, we present a series of 3 neonates with CPA managed at our center in the year 2020 (Jan 2020-December 2020). The associated skin blisters in all 3 cases likely represent Carmi syndrome. It is the name given to a rare genetic disorder characterized by junctional epidermolysis bullosa (JEB) and pyloric atresia (PA). While one succumbed before any intervention, 2 of them underwent surgery. Though isolated CPA has a good prognosis, Carmi syndrome has a poor outcome, as observed in our series. We are presenting 3 neonates with likely Carmi syndrome, emphasizing that genetic screening and counseling are necessary in these cases.

Case 1

A 3-day-old, premature (34 weeks of gestation) male neonate was admitted to the neonatal ICU with multiple blisters over the body. Pediatric surgical opinion was sought in view of feed intolerance and non-bilious vomiting. X-ray abdomen showed a classical single bubble shadow without any distal gas (Fig. 1A). A diagnosis of CPA with associated Epidermolysis bullosa was made. The blood picture was suggestive of leukocytosis (18000 cells/mm3) (with a neutrophilic predominance of 78%) and thrombocytopenia (Platelet counts-40000 cells/mm3). C-reactive protein was raised (22 mg/dl). Blood culture revealed Acinetobacter sp., sensitive to Colistin. The child succumbed to sepsis before any surgical intervention could be done.

Case 2

A 7-day-old, full-term gestation male baby presented with complaints of multiple blisters over the body and inability to feed. The initial history given by attendants pointed to a thermal injury by the warmer. X-ray abdomen was suggestive of classical pyloric atresia, and in association with skin blisters, a retrospective diagnosis of associated Epidermolysis bullosa was made. Exploratory laparotomy revealed Type 2 CPA (Fig. 1B) and retro-colic posterior gastrojejunostomy (GJ) was done, after excluding distal atresia. The neonate did not tolerate feeds in the post-operative period and had multiple episodes of bilious vomiting. The baby underwent re-exploration after waiting for 2 weeks and loop GJ was converted to Roux-en-Y GJ. Oral feeds were started on POD 3 and discharged by POD-7. The baby was lost to follow-up after 2 months of age. A later inquiry over the phone revealed that the baby had succumbed at the age of 3 months to an unknown cause.

Case 3

A preterm (33 weeks of gestation), low birth weight (1.2 kg) male baby was brought on day 2 of life with upper abdominal distension, skin blisters, and vomiting of milk (Fig. 1C). X-ray abdomen showed a single bubble appearance and a diagnosis of CPA with Epidermolysis bullosa was made. Laparotomy revealed type 1 CPA for which Heineke-Mikulicz pyloroplasty with diaphragm excision was done, after confirming distal patency of the bowel. Oral breastfeeds were started on POD-5. The discharge from the hospital was delayed due to the development of Acinetobacter sepsis, with blood picture showing raised CRP (42 mg/dl), and leukocytosis (TLC-19500 cells/mm3) with thrombocytopenia (Platelet counts- 45000 cells/mm3). 2D-Echo and ultrasound abdomen ruled out associated cardiac and renal anomalies.(Table 1)

CPA is known to occur in 1 in 100000 live births. It constitutes about 1% of all gastrointestinal atresia. It equally affects male and female patients.^[1] CPA has been associated with low birth weight and polyhydramnios, each reported in up to 60% of the patients.^[2] Antenatal ultrasound may raise suspicion of CPA as early as 10 weeks, with polyhydramnios and dilated stomach shadow.

CPA was first reported in the year 1749 by Calder. It may present as an isolated anomaly or be associated with other systemic anomalies. There are 3 types of CPA. In type 1, there exists a pyloric membrane or diaphragm at the pylorus. The pyloric tissue is replaced by a solid cord of tissue in type 2 CPA. Type 3 CPA is characterized by a mesenteric gap between the stomach and duodenum. The type 1 CPA is the most common type of CPA (57%) while the type 3 CPA is the rarest (9%).

The etiology of CPA is largely unknown. Embryologically, it occurs due to developmental aberration at 5 to 12 weeks of gestation.^[3] The most accepted theory of failure of canalization of a pyloric tube was given by Tandler.^[4] Lowe and Bernard proposed a mechanical cause or vascular accident as an etiology, similar to jejunoileal atresia.^[5] Weber ^[6] and Chang et al. ^{[7], [8]} explained the association between CPA and Epidermolysis bullosa and proposed that this association results from an intrauterine mucosal injury at junctional EB, with subsequent ulceration and inflammatory response.

Other associated anomalies like ureteral and renal anomalies (duplicated pelvicalyceal system, hydronephrosis/hydroureteronephrosis, dysplastic or multicystic kidney, or/and absent bladder), milia, nail dystrophy, aplasia cutis congenita, esophageal atresia, and multiple colonic atresias have been reported in 40–55% of the cases.^{[9], [10]} There were no other associated anomalies in our 2 operated cases.

The treatment of CPA is governed by the type of atresia. Type 1 and 2 CPA are treated using the technique of Heineke–Mikulicz pyloroplasty (excision of membrane/tissue followed by transverse closure of longitudinally opened canal). For type 3 CPA, the treatment of choice is gastro-duodenostomy or gastro-jejunostomy. Per-operatively, the patency of the distal intestine needs to be confirmed to exclude associated distal intestinal atresia. Isolated CPA has a good prognosis. The mortality exceeds 50% when associated with severe and often fatal anomalies.^[9]

Carmi Syndrome is the name given to an association of epidermolysis bullosa (EB) and congenital pyloric atresia (CPA).^[11] EB is a group of hereditary skin disorders with characteristic vesicular lesions at or shortly after birth, targeted to areas of friction/minor trauma. It is categorized as EB simplex (EBS), junctional EB (JEB), and dystrophic EB (DEB). EB has sub-epidermal separation through the lamina lucida causing mechano-bullous lesions and is generally fatal. EB has genetic predilections and may run in families. The decision regarding the prognosis and future pregnancies should be discussed with the parents, along with genetic counseling. It is possible to diagnose EB by the electron microscopy of fetal-skin biopsy, carried out at 19 weeks gestation. ^[12] The parents of case 2 of our series had revealed over the phone that they recently had another sibling with similar features (Carmi Syndrome) but could not be operated on in view of travel restrictions due to the Covid pandemic and expired at home. The family was advised for genetic counseling. A tabular presentation of reported Carmi syndrome in Literature is shown in Table 2.

The incidence of EB alone is 1/300,000. Healthy long-term survival is documented in the literature despite high mortality with this combination.^[7] EB has no definitive treatment, usually managed with supportive care. It includes derma care of lesions, with appropriate dressing and infection control. Nutritional supplements and topical steroids may be used for local inflammation. One of the operated cases expired after loss to follow-up (most likely due to sepsis) and another is in follow-up for the last 1.5 years and gaining weight, without any recurrence of skin lesions.

A systematic literature review of Carmi syndrome by Mylonas KS et al included 100 patients out of 63 studies that showed an equal prevalence of type 1 and 2 CPA. Overall mortality was 74.5%, with 50% of deaths occurring in the neonatal period. Out of 73 patients who underwent surgery, 49 died (67.1%).^[13] They suggested that detailed genetic mutation studies can be used to guide surgical intervention, as well as family planning. Hon KL et al reported late deaths in 3 cases of EB and found on a review of the literature that sepsis/septicemia is one of the common causes of death in these patients and stressed active skin care.^[14]

Carmi syndrome should be kept as a differential diagnosis in neonates with skin blisters and feed intolerance. Early recognition and prompt medical and surgical management do contribute to a successful outcome. We propose that all neonates presenting with congenital pyloric atresia should be screened for multiple anomalies and undergo skin biopsy (at the time of surgery) with immunofluorescence microscopy to describe the type of associated EB for prognostication. Genetic screening should be offered to parents of babies with CPA with the syndromic association.