History of Present Illness

1
History of Present Illness

• An 11-month old male presents with severe failure
  to thrive, chronic diarrhea, and hepatomegaly.

2
History of Present Illness

• The patient was born full-term with a birth
  weight of 2.8 kg and did not regain his birth
  weight until 2 months of age.
• He had foul-smelling diarrhea after every feed
  for most of his life.
• He was seen by an endocrinologist at 4 months of
  age for poor weight gain, but no diagnosis was
  found. It was noted at the time that he had a
  mildly enlarged liver.

3
History of Present Illness

• His weight and height paralleled (but were both
  under) the 3rd percentile curve.
• He was started on table foods at 7 months of age
  and began Pediasure at 9 months without
  improvement in his weight gain.
• No vomiting, arching, fever, jaundice, or rashes
  were reported.

4
History

• Past medical history occipital nodal abscess at
  age 5 months and RLL pneumonia at age 10 months,
  both rapidly responding to antibiotics.
• No prior surgeries.
• Medications Zantac for presumed reflux.
• Allergies none

5
History

• Social hx no known consanguinity, parents are
  from Puerto Rico.
• Family hx noncontributory, 6-yo brother with no
  medical problems.
• Developmental hx delayed, not able to sit
  without support.
• Birth hx born at 38 weeks gestation via
  scheduled C-section, no complications.

6
Physical Exam

• Weight 5.16 kg (ltlt 3rd ile, 50th ile for 2
  months)
• Height 62.5 cm (ltlt 3rd ile, 50th ile for 3
  months)
• Vital signs WNL
• General small, wasted-appearing infant with a
  high-pitched cry
• HEENT gray teeth, no scleral icterus
• Chest narrow thorax, lungs clear to auscultation
  bilaterally
• Heart regular rate, nlS1S2, no murmurs

7
Physical Exam

• Abdomen protuberant, liver palpable 3 cm below
  RCM, spleen not palpable, normal bowel sounds
• Extremities WNL
• Skin no jaundice
• Neuro mild hypotonia

8
Labs

• Electrolytes normal
• Total bili 0.3 mg/dl, total protein 8.7 g/dl,
  albumin 4.7 g/dl, alk phos 162, ALT 365, AST 325,
  GGT 63 Cholesterol 88 Uric Acid 3.7, amylase lt
  30, lipase 20
• WBC 20.9, Hgb 11.3 g/dl, Hct 35, Plts 472, MCV
  86.6, 87 Lymphs, 3 Seg, ANC 627
• PT 13.6 PTT 36.4 INR 1.2

9
Labs

• Stool reducing substances were negative, stool pH
  5.5
• Urinalysis positive nitrites, positive leukocyte
  esterase, 5-10 WBCs, small bacteria
• Urine culture E. coli
• Stool studies including culture, ova and
  parasites, and C. difficile were negative.

10
Studies

• Abdominal ultrasound
• Echogenic pancreas possibly representing fatty
  infiltration.
• Normal appearance of liver and biliary tree.
• Nephrocalcinosis with multiple nonobstructing
  kidney stones.

11
Discussion
12
Differential Diagnosis

• Cystic fibrosis
• Shwachman-Diamond syndrome
• Celiac disease
• Viral hepatitis
• Alpha-1 antitrypsin deficiency
• Metabolic disorders (galactosemia, tyrosinemia)
• Pearsons syndrome
• Johanson-Blizzard syndrome

13
More Labs/Studies

• Sweat test was within normal limits
• Stool fecal elastase was lt 15 ug/g (200-500),
  suggesting severe exocrine pancreatic
  insufficiency.
• 72-hour quantitative fecal fat 8 grams/24 hrs
  (normal 0-2 grams/24 hrs)
• Viral hepatitis panel was negative.
• Celiac panel was normal.
• Serum amino acids, urine organic acids were
  unremarkable.

14
More Labs/Studies

• Bone marrow aspirate revealed myeloid asynchrony
  not diagnostic of a specific pathologic entity,
  but could be consistent with a bone marrow
  failure syndrome such as cyclic neutropenia or
  Shwachman-Diamond syndrome.
• Skeletal survey showed a delay in skeletal
  maturation in the femurs, a narrow thoracic cage,
  and mild thickening of the anterior ribs.

15
More Labs/Studies

• Genetic testing showed two mutations in the SBDS
  gene consistent with the diagnosis of
  Shwachman-Diamond syndrome.

16
Shwachman-Diamond Syndrome

• Shwachman-Diamond syndrome (SDS) is a rare
  autosomal recessive disorder characterized by
  exocrine pancreatic dysfunction, bone marrow
  failure, and skeletal abnormalities.
• Also known as Shwachman syndrome,
  Shwachman-Bodian syndrome, and congenital
  lipomatosis of the pancreas.

17
Shwachman-Diamond Syndrome

• Described by Shwachman, Diamond, Oski, and Knaw
  in 1964 with five children showing evidence of
  exocrine pancreatic insufficiency and leukopenia.
• Burke et al (1967) and Pringle et al (1968)
  observed associated skeletal changes of the
  metaphyseal dysostosis type, which became the
  third fundamental feature of the syndrome.

18
Shwachman-Diamond Syndrome

• The most common cause of pancreatic insufficiency
  in children next to cystic fibrosis
• Probably the most common inherited bone marrow
  failure syndrome after Fanconis anemia and
  Diamond-Blackfan anemia.

19
Epidemiology

• Incidence is estimated at 1 in 50,000 in North
  America.
• Slight male predominance (1.71 malefemale
  ratio)
• Reported among all racial and ethnic groups.
• Usually diagnosed during infancy when patients
  present with malabsorption and recurrent
  infections.

20
Pancreatic insufficiency

• All patients with SDS have varying degrees of
  pancreatic insufficiency.
• In these patients, pancreatic acinar cells do not
  develop in utero and are replaced by fatty
  tissue. In contrast to CF, the pancreatic ductal
  architecture is spared, and there is preservation
  of ductular output of fluid and electrolytes.

21
Pancreatic insufficiency

• The pancreatic lipase secretion increases
  slightly with age in patients with SDS, resulting
  in decreased fat excretion.
• Approximately 50 of affected patients will show
  enough improvement in pancreatic acinar capacity
  with increasing age so that pancreatic enzyme
  supplementation becomes unnecessary.

22
Failure to Thrive

• Fat malabsorption contributes to failure to
  thrive in SDS patients.
• Other factors contributing to failure to thrive
  include recurrent infections, skeletal
  abnormalities, and decreased or absent growth
  hormone levels.

23
Hematologic Abnormalities

• Pathogenic defect responsible for hematologic
  abnormalities is unknown.
• Almost 50 of patients with SDS have
  pancytopenia.
• Other patients have variable degrees of anemia,
  thrombocytopenia, or neutropenia.
• ANC may be intermittently or persistently low in
  more than 95 of patients.

24
Hematologic Abnormalities

• Patients with SDS have defective neutrophil
  chemotaxis, linked to a defect in chromosome 7.
• Myelodysplastic syndromes and acute leukemias
  develop in up to a third of patients.

25
Skeletal Abnormalities

• More than 75 of patients with SDS have skeletal
  anomalies
• Delayed appearance but normal shape of epiphyses
• Progressive thickening of metaphyses
• Osteopenia
• Severity and localization of anomalies vary with
  age.
• Exact pathophysiology of skeletal abnormalities
  is not known.

26
Clinical Presentation

• Typical presentation of SDS is diarrhea, short
  stature, failure to thrive, and recurrent
  infections.
• Average birth weight is usually low (2.9 kg /-
  0.5 kg) and by 6 months of age the mean heights
  and weights are usually below the 5th percentile.

27
Clinical Presentation

• Imperforate anus and Hirschsprung disease have
  been seen in some patients with SDS, which may
  delay the diagnosis of SDS because the patient
  will present with constipation instead of
  diarrhea.

28
Clinical Presentation

• Recurrent infections
• Upper respiratory tract infection
• Otitis media
• Sinusitis
• Pneumonia
• Osteomyelitis
• Urinary tract infection
• Bacteremia
• Skin infection
• Aphthous stomatitis
• Fungal dermatitis
• Paronychia

29
Clinical Presentation

• Skeletal abnormalities
• Coxa vara deformity
• Genu and cubitus valgus
• Clinodactyly
• Syndactyly
• Supernumerary metatarsals
• Dental abnormalities

30
Clinical Presentation

• Dermatologic abnormalities include eczema,
  ichthyosis, and petechiae.
• Pallor, easy bruising, epistaxis, GI bleeding can
  be seen.
• Delayed puberty
• Mild-to-moderate psychomotor or developmental
  delay can be seen in up to 15 of patients with
  SDS.
• Diabetes and renal abnormalities have been
  reported.

31
Clinical Presentation

• Hepatic involvement in children with SDS is
  common.
• Elevated transaminases
• Hepatic steatosis
• Mild portal fibrosis
• Progressive liver dysfunction is rare. Cirrhosis
  has been reported as incidental findings at
  autopsy in occasional cases.

32
Clinical Presentation

• On exam, patients often appear emaciated with
  abdominal distension accentuated by hypotonia and
  hepatomegaly.

33
Laboratory Studies

• Anemia, thrombocytopenia, and/or neutropenia
• 72-hour fecal fat measurement often shows an
  increase in fecal fat losses.
• Sweat test normal
• Transaminases may be elevated, low albumin can be
  seen from malabsorption, normal bilirubin and
  coagulation studies.
• Growth hormone levels are often decreased.

34
Imaging Studies

• Ultrasound of the pancreas can show a normal size
  pancreas with increased echogenicity.
• CT scan can show lipomatosis of the pancreas.

35
Imaging Studies

• Skeletal survey may reveal
• Delayed bone age
• Thoracic dysostosis
• Costochondral thickening
• Short flaring lower ribs
• Narrow thoracic cage
• Shortening of extremities, metaphyseal widening
• Tubulation of the long bones (especially ulna,
  tibia)
• Valgus deformities of the elbows and knees.

36
Bone Marrow Studies

• Periodic bone marrow evaluation studies can show
  bone marrow failure and leukemic transformation.

37
Biopsies

• Pancreas biopsies (not routinely indicated) may
  reveal mostly adipose tissue containing the
  islets of Langerhans with very few elements of
  exocrine gland structure present.
• Liver biopsies may show periportal and portal
  inflammation and fibrosis, micro and
  macrovesicular steatosis, mononuclear infiltrate,
  and occasional fibrous bridging between portal
  tract areas.

38
Diagnosis

• Clinical diagnosis of SDS can be difficult due to
  disease heterogeneity.
• Exocrine pancreatic dysfunction and bone marrow
  dysfunction are considered to be requirements for
  establishing a clinical diagnosis.
• Genetic analysis can be used for diagnostic
  confirmation.

39
Genetics of SDS

• Autosomal recessive
• Mutations of the SBDS (Shwachman-Bodian-Diamond
  syndrome) gene at chromosome 7q11 are present in
  the majority of patients with SDS.
• Most of the SBDS mutations are thought to
  truncate the SBDS protein, suggesting they act in
  a loss-of-function manner.
• Function of the SBDS gene remains unknown.

40
Treatment of SDS

• Main components of treatment
• Pancreatic enzyme supplementation
• Prevention or treatment of infections
• Correction of hematologic abnormalities
• Prevention of orthopedic deformities
• Fat soluble vitamins, medium-chain triglycerides,
  and other high-calorie supplements may be needed.
• Bone marrow transplant is the only curative
  therapy for severe hematologic manifestation of
  SDS.

41
Prognosis of SDS

• In general, the majority of patients with SDS
  enjoy relatively good health.
• In a significant number of patients, pancreatic
  function, infection, and hepatic dysfunction
  decline with time.

42
Prognosis of SDS

• Very limited information exists on long-term
  survival in SDS.
• Leading causes of death include sepsis, leukemia,
  and bone marrow failure.
• Alter et al (1998) reported projected median
  survival ages
• gt35 years for all patients with SDS
• 24 years for patients whose course is complicated
  by aplastic anemia.
• 10 years for patients whose course is complicated
  by leukemia.

43
Other Inherited Syndromes With Pancreatic
Insufficiency

• Johanson-Blizzard syndrome
• Autosomal recessive
• Characterized by pancreatic insufficiency and
  growth retardation with lipomatous transformation
  of the pancreas.
• Also has thyroid dysfunction, aplastic alae nasi,
  cardiac anomalies, genitourinary malformations,
  deafness, absence of permanent teeth, and
  imperforate anus.
• Preservation of pancreatic ductular output of
  fluid and electrolytes like in SDS, but unlike
  CF.
• No skeletal or hematologic abnormalities like in
  SDS.

44
Other Inherited Syndromes With Pancreatic
Insufficiency

• Pearsons syndrome (aka Pearson Marrow-Pancreas
  syndrome)
• Multisystem mitochondrial disorder of early
  childhood.
• Characterized by pancreatic insufficiency,
  refractory sideroblastic anemia, variable degrees
  of neutropenia and thrombocytopenia, and
  vacuolization of bone marrow precursors.
• Underlying defect is due to mitochondrial
  respiratory chain dysfunction secondary to
  rearrangements of mitochondrial DNA (mtDNA).
• More likely to be associated with diabetes
  mellitus.

45
Patient Course

• MRI of the brain showed a Chiari I malformation
  with obstructive hydrocephalus.
• A ventriculoperitoneal shunt was placed by
  neurosurgery.
• Voiding cystourethrogram showed left-sided grade
  II vesicoureteral reflux.

46
Patient Course

• The patient was discharged on pancreatic enzyme
  supplements and fat soluble vitamins and
  proceeded to gain weight.
• Due to rising transaminases, a liver biopsy was
  done which showed mild focal and lobular
  inflammation that were nonspecific, but
  consistent with SDS.

47
I have found from experience that atypical cases
usually turn out to be typical cases of something
else. The job is to identify the something
else. -Louis Diamond, 1960