Introduction

Multiple molecular diagnoses may be more common than previously thought and occurred in ~ 4.9% of patients who were referred for whole genome sequence analysis [1].

Homozygous sickle cell disease (SS disease) is an autosomal recessive genetic disorder [2] with a variable phenotype and is common in many areas of the world [3]. Waardenburg syndrome type 4 (WS4) or Waardenburg-Shah syndrome is a rare disease globally, with less than 80 reported cases [4]. WS4 syndrome may be autosomal recessive or autosomal dominant, and a feature of this disorder is Hirschsprung’s disease [5].

We report a rare case of the co-inheritance of both SS disease and WS4 who presented to a specialist Sickle Cell Center (SCC). This case report is unusual as it is believed that this may be the first reported case to describe the blended phenotype of WS4 and SS disease and draws attention to the need for the further investigation of patients with one genetic disorder who present with atypical features. The report may raise awareness of the co-occurrence of SS disease and WS4.

Case presentation

We present the case of an Afro-Caribbean woman who died at age 54 years. In addition to being mute her primary complaints on first presentation at age 7 were congenital deafness, jaundice, and constipation (Table 1). In addition, there was a history of snoring without mention of apnea. A history of similar congenital deafness and pigment abnormalities was reported in distant cousins. A half-sister who predeceased her had also been diagnosed as having SS disease. There was no previous history of pain or other sickle cell-related complications at this time.

Table 1 Timeline of major clinical events for case study
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On physical examination at first presentation at 7 years of age, she was afebrile and was found to be markedly icteric. She did not have a white forelock (Fig. 1) but was noted to be deaf, mute, and with blue eyes (Fig. 1) in keeping with her diagnosis of Waardenburg syndrome (WS). On abdominal examination, a hard mass was found; the dimensions were not described but it was thought to be a fecalith. In addition, her liver was documented as three fingers breadth below her right costal margin, a span was not documented. At that time she was diagnosed as having WS; acute cholestasis and SS disease were suspected. The diagnosis of SS was supported by a hemoglobin electrophoresis (Table 2), in addition to her previous diagnosis of WS. A later study revealed heterozygous deletional alpha thalassemia (Table 2), which is considered to be protective in persons with SS disease as persons with this trait tend to have less severe disease. At the time her hemoglobin level was 7.4. Of note, this varied from 7.5–8.2 g/dL up to an age of 39 years and fell to 6.0 g/dL in later years. Genetic testing for genetic mutations associated with WS4 was not possible because of availability. The results of hearing tests were not documented but she attended a school for the deaf and communicated by writing.

Fig. 1
figure 1

Patient as a child (a) and as an adult (b); note blue irides and icteric conjunctivae. Photo from childhood (a) was taken by the late Dr Paul Milner

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Table 2 Diagnostic assessments and recorded results for the patient in chronological order
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Surgical interventions included tonsilloadenoidectomy at 8 years due to upper airway obstruction. The post-surgery period was complicated with chest complications likely to have been acute chest syndrome. In addition, a Duhamel procedure bypassing the rectum was performed at age 9. This was preceded by prolonged history of recurrent presentations for constipation requiring fecal disimpaction under anesthesia. An acquired megacolon was diagnosed with a barium enema and total colonic aganglionosis had been diagnosed after two high rectal biopsies (Table 2) which led to the diagnosis of Hirschsprung’s disease with subsequent correction.

Follow-up visits at the SCC (Table 1) revealed other complaints which were mainly related to both WS and SS disease. Sickle cell-related complications included a bone pain episode which was first documented at 8 years of age. One to two bone pain crises were documented annually. She was treated mainly as an out-patient with acetaminophen, nonsteroidal anti-inflammatory agents, and occasionally opioids without adverse reaction. At her first presentation, pain and swelling of the dorsum of both hands were noted on physical examination and there was a limited range of movements at her wrists. A diagnosis of avascular necrosis was made. An important outcome of this was a shortened left fourth metacarpal diagnosed at 15 years. This is typical of infection complicating dactylitis (hand-foot syndrome). Although she complained of hip pain at 18 years of age, X-rays of her left hip showed no changes until 53.9 years when sclerotic changes suggestive of avascular necrosis were seen (Table 2).

At 18 years of age she complained of hair loss including eyebrows. As a result, she chose to wear a wig in adulthood (Fig. 1). She was referred to a dermatology clinic. Documented treatment included hair pomade. At 33 years she also complained of a chronic right leg ulcer and symptomatic gallstones in her later years requiring cholecystectomy.

At her last visit to the SCC, 3 weeks prior to her death, she complained of pain, cough, weight loss, and episodes of vomiting and was admitted to hospital with a diagnosis of acute chest syndrome and painful crisis. Her renal function was impaired (Table 2), and blood pressure was elevated (179/80 mmHg). Her hemoglobin was 4.5 gm/L and she was given a red blood cell transfusion and parenteral antibiotics. She later died in the intensive care unit.

Discussion

The authors described a case of an Afro-Caribbean woman with co-inheritance of homozygous SS disease and WS. This case describes the features of this unusual phenotype.

Her morbidity pattern suggests that these diseases were inherited as separate disorders without overlap, and is referred to as a blended phenotype. The co-inheritance in this patient may be attributable to the worldwide distribution of both diseases. SS disease is common in the Caribbean, Africa, and Asia, with an incidence of 1 in 150 live births in Jamaica [6]. WS is seen in Northern Europe but the highest incidence is reported among Kenyan Africans [7].

This patient was atypical in the absence of a white forelock of hair or hair depigmentation and although alopecia is not a diagnostic criterion for WS4, congenital alopecia totalis has been reported with Hirschsprung’s disease [8]. Previously reported cases of WS4 have been diagnosed in the neonatal period [9, 10] and the Duhamel procedure in our case was performed relatively late.

Her age at death, 54 years, is above the median survival reported in a recent study of a Jamaican cohort [11], but lower than the 53 years for men and 59 years for women estimated from an earlier study [12]. The inheritance of alpha thalassemia trait and SS disease is associated with less severe disease [13, 14] and may have contributed to her relatively mild course in earlier years. Although sensorineural hearing loss may occur in SS disease [15], it is usually age related and not congenital as in WS4 syndrome. This was not considered to contribute to the congenital deafness experienced by our patient.

This report is limited by the inability to carry out whole exome genomic sequencing but, in the absence of this investigation, both diseases originate from very different molecular pathways and the phenotype in this case was typical of each disease.

Conclusions

In conclusion, persons with a known molecular diagnosis need to be investigated if there are atypical findings. The delayed diagnosis of SS disease demonstrates that other genetic disorders should be considered in patients who already have the diagnosis of one Mendelian disorder but show atypical features.