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 .
Homozygous sickle cell disease (SS disease) is an autosomal recessive genetic disorder  with a variable phenotype and is common in many areas of the world . Waardenburg syndrome type 4 (WS4) or Waardenburg-Shah syndrome is a rare disease globally, with less than 80 reported cases . WS4 syndrome may be autosomal recessive or autosomal dominant, and a feature of this disorder is Hirschsprungs disease .
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.
Timeline of major clinical events for case study
Relevant past medical history and interventions
This patient was known to have a history of Waardenburg syndrome. She had a family history of congenital deafness and pigment abnormalities. A half-sister who predeceased her had also been diagnosed with SS disease
Summaries from initial and follow-up visits
Diagnostic testing (including dates)
Presented with jaundice. Diagnosed as having SS disease, in addition to Waardenburg syndrome
Referred to a specialist unit for sickle cell disease
High rectal biopsy
Bone pain crisis, suspected acute chest syndrome
Complete blood count
Buscopan (hyoscine butylbromide) 20mg intramuscularly, Gravol (dimenhydrinate) 50mg intramuscularly, and codeine 60mg orally as immediate doses
Diagnostic assessments and recorded results for the patient in chronological order
Complete blood count
Hb 7.5g/dL, MCV 78fl, retics 0.05 (proportion of red blood cells), WBC 24.0109/L, platelets 250109/L
Abundant muscle, numerous nerve fibers but no ganglion cells.
Rectal biopsy (lowest value)
No ganglion cells were seen. A few dubious nerve fibers were observed.
Plain radiograph left hip
Alpha globin gene number
Heterozygous deletional alpha thalassemia
Plain radiograph left hip
Sclerotic changes to head of femur and trochanteric area. Decreased joint space, osteophytic changes
Urea and electrolytes
K 5.8mmol/L, creatinine 153mol/L (reference males 80mol, females 68mol), Nai134mmol/L, Cljmmol/L, HCO3-12mmol/L
Complete blood count
Hb 6.0g/dL, MCV 78fl, retics 0.05 (proportion of red blood cells), WBC 12.0109/L, platelets 262109/L. (Last SCC presentation 9 March 2012)
Surgical interventions included tonsilloadenoidectomy at 8years 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 (Table2) which led to the diagnosis of Hirschsprungs disease with subsequent correction.
Follow-up visits at the SCC (Table1) 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 8years 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 15years. This is typical of infection complicating dactylitis (hand-foot syndrome). Although she complained of hip pain at 18years of age, X-rays of her left hip showed no changes until 53.9years when sclerotic changes suggestive of avascular necrosis were seen (Table2).
At 18years 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 33years 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 (Table2), and blood pressure was elevated (179/80mmHg). 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.
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 . WS is seen in Northern Europe but the highest incidence is reported among Kenyan Africans .
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 Hirschsprungs disease . 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, 54years, is above the median survival reported in a recent study of a Jamaican cohort , but lower than the 53years for men and 59years for women estimated from an earlier study . 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 , 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.
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.
- SCC:Sickle Cell Center
- SS disease:Homozygous sickle cell disease
- WS:Waardenburg syndrome
- WS4:Waardenburg syndrome type 4 or Waardenburg-Shah syndrome