Table 3.

Genetic Disorders in the Differential Diagnosis of Cystic Fibrosis

Gene(s)DisorderMOIKey FeaturesComment / Distinguishing Features
~45 genes incl:
CCDC39
CCDC40
CCDC103
DNAH5
DNAH11
DNAI1
ODAD2 (ARMC4)
ODAD3
(CCDC151)
SPAG1
ZMYND10		Primary ciliary dyskinesia (PCD)See footnote 1.
  • Abnormal ciliary structure & function (→ retention of mucus & bacteria in respiratory tract) & abnormal flagellar structure (→ abnormal sperm motility);
  • Respiratory distress in infancy; cough & sputum production w/recurrent pneumonias that may progress to chronic bronchiectasis; Pseudomonas aeruginosa or other opportunistic bacterial pathogens; chronic sinus disease
  • Situs inversus is present in 50% of persons w/PCD.
  • Steatorrhea & poor weight gain are not assoc w/PCD.
  • 20%-30% of persons w/well-characterized PCD do not have identifiable pathogenic variants in any known PCD-related genes.
BTK X-linked agammaglobulinemia (XLA)XL
  • Recurrent bacterial infections in affected males in 1st 2 yrs of life – most commonly recurrent otitis media
  • Conjunctivitis, sinopulmonary infections, diarrhea, & skin infections are also frequently seen.
Persons w/XLA are also prone to life-threatening infections (e.g., meningitis, sepsis, cellulitis, or septic arthritis) not specifically seen in CF.
C2 2
CARD11 3
CD19 4
CD81 5
CR2
(CD21) 6
CTLA4 7
CXCR4 8
ICOS 9
IKZF1 10
IL21 11
IRF2BP2 12
LRBA 13
MS4A1 14
NFKB1 15
NFKB2 16
PLCG2 17
PRKCD 18
SKIC3
(TTC37) 19
STAT3 20
TNFSF12 21
TNFRSF13B 22
TNFRSF13C 23
TRNT1 24		Common variable immunodeficiencyAD
AR
  • Recurrent lung, sinus, & ear infection; recurrent lung infections can lead to chronic lung disease (bronchiectasis).
  • Diarrhea & impaired nutrient absorption
Recurrent or chronic Giardia lamblia infection of small intestine; lymphadenopathy; splenomegaly; ↑ risk of cancer of lymphatic tissues & gastric cancer; granular inflammatory nodules w/in skin, lung spleen, & liver
CA12 Isolated hyperchlorhidrosis (OMIM 143860)AR↑ sweat chloride levels, poor weight gain, growth deficiencyCan lead to severe infantile hyponatremic dehydration & hyperkalemia
DNAJC21
EFL1
SBDS
SRP54 		Shwachman-Diamond syndrome (SDS)AR
AD 25		Exocrine pancreatic dysfunction w/malabsorption, malnutrition, & growth failureSDS can be distinguished from CF by presence of hematologic abnormalities w/single- or multilineage cytopenias, susceptibility to MDS & AML, & skeletal abnormalities.
IL2RG X-linked severe combined immunodeficiency (X-SCID)XL
  • Typical X-SCID: w/universal NBS for SCID, common presentation is asymptomatic, healthy-appearing male infant.
  • Atypical X-SCID: usually not detected by NBS; can manifest in 1st yrs of life or later w/recurrent upper & lower respiratory tract infections w/bronchiectasis
  • Persons w/X-SCID are also prone to nonrespiratory infections (e.g., otitis media, cellulitis) not specifically assoc w/CF.
  • Other features may incl, e.g., hepatosplenomegaly, lymphadenopathy, lymphopenia.
NR3C2
SCNN1A
SCNN1B
SCNN1G 		Pseudohypoaldosteronism type I (OMIM 177735 & 264350)AR
AD 26
  • Defect in epithelia sodium channel or mineralcorticoid receptor protein
  • ↑ sweat chloride in some persons
  • Chronic bronchitis, bronchiectasis, recurrent pulmonary infections
Normal exocrine pancreatic function

AD = autosomal dominant; AML = acute myelogenous leukemia; AR = autosomal recessive; CF = cystic fibrosis; MDS = myelodysplasia syndrome; MOI = mode of inheritance; NBS = newborn screening; XL = X-linked

1.

PCD is usually inherited in an autosomal recessive manner. PIH1D3-related PCD and OFD1-related PCD are inherited in an X-linked manner. FOXJ1-related PCD is inherited in an autosomal dominant manner.

2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.

SDS caused by pathogenic variants in DNAJC21, EFL1, or SBDS is inherited in an autosomal recessive manner. SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner.

26.

Pseudohypoaldosteronism caused by pathogenic variants in SCNN1A, SCNN1B, or SCCN1G is inherited in an autosomal recessive manner. Pseudohypoaldosteronism caused by pathogenic variants in NR3C2 is inherited in an autosomal dominant manner.

From: Cystic Fibrosis

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