Table 5.
Clinical summary of patients with CDKN1B variants of interest
| Case no. | CDKN1B variant (origin) | Gender | Race (country of origin) | Age at disease onset/age at diagnosis (years) | Clinical presentation | Biochemistry | Tumor description | Genetic findings in tumor | Treatment and outcomes | Relevant family history | Age at last follow-up (years) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | c.-29_-26delAGAG, p.? heterozygous (unknown: father n/a, mother wild type). | M | White (USA). | 10/13.6 | Poor linear growth (height -1.7 SDS at first visit), weight gain with central distribution (weight 0.7 SDS, but BMI in the 95th percentile), fatigue, headaches, red striae, dorsocervical fat pad, acanthosis nigricans, hypertension. | Midnight serum cortisol: 20.5 µg/dL; UFC: 156.3 µg/24 h (2.8 × ULN); CRHST: 156.1% increase in cortisol and 258.1% increase in ACTH; BIPSS: 9.6 central/peripheral and 5.5 right/left ACTH ratios. | 3 mm microadenoma (corticotropinoma), no extrasellar extension. | No LOH for CDKN1B variant. USP8 hotspot wild type. | TSS ×1, remission after surgery. | History of hypercholesterolemia in the father. | 14.7 |
| 2 | c.320delA, p.Q107Rfs*12 heterozygous (maternal). | M | White (USA). | 12.5/15.8 | Weight gain with central distribution (weight +2.7 SDS at first visit), poor linear growth (height -1.9 SDS), tinea corporis, proximal muscle weakness, dorsocervical fat pad, thoracic scoliosis, stress fracture of right foot, hypertension. Additional diagnoses: Gilbert’s syndrome, transient ischemic attack, right hydrocele and left epididymal cyst (right testicular biopsy reported normal tissue). | Midnight serum cortisol: 15.6 µg/dL; UFC: 571 µg/24 hours (6.3 × ULN); serum cortisol post-LDDST: 2 µg/dL; CRHST: 127.5% increase in cortisol and 180.4% increase in ACTH; BIPSS: 82.2 central/peripheral and 8.1 right/left ACTH ratios. | 4 mm microadenoma (corticotropinoma), no extrasellar extension. | n/a | TSS ×1, remission after surgery, no evidence of recurrence at age 36 years. | Mother had hypertension, type 2 diabetes mellitus and hypercholesterolemia; deceased due to colon adenocarcinoma, carrier of CDKN1B variant (LOH for CDKN1B variant in primary tumor and liver metastasis tissues). Brother and two children of the patient are apparently healthy carriers of CDKN1B variant. | 36.4 |
| 3 | c.356T>C, p.I119T heterozygous (unknown origin: DNA samples from parents n/a). | F | White (USA). | 10/13.8 | Weight gain with central distribution (weight 4.8 SDS with height –0.5 SDS at first visit), hirsutism, type 2 diabetes mellitus, hypertension.a | Midnight serum cortisol: 7.9 µg/dL; UFC: 148 µg/24 hours (2.6 × ULN); CRHST: 116% increase in cortisol and 533.5% increase in ACTH; BIPSS: 92.4 central/peripheral and 14.2 right/left ACTH ratios.a | 8 mm microadenoma (corticotropinoma) with extension to left cavernous sinus. | No LOH for CDKN1B variant. USP8 p.P720R heterozygous. | TSS ×2, remission after second surgery. | Not significant. | 14.8 |
| 4 | c.376G>C, p.E126Q heterozygous (unknown origin: DNA samples from parents n/a). | F | Unknown (Iraq). | 9/12 | Weight gain with central distribution, hair loss, striae and headaches. | 8 AM serum cortisol: 25 µg/dL; 8 AM ACTH: 274.5 pg/mL; serum cortisol post-LDDST: 20.3 µg/dL. | 5 mm microadenoma (PitNET, no IHC), no extrasellar extension. | n/a | TSS ×1, remission after surgery. | Parents are first cousins (CGH: regions of homozygosity detected, consanguineous parents). Family history of obesity, diabetes and hypertension in multiple members of the family. | 14 |
| 5 | c.407A>G, p.D136G heterozygous (unknown origin: DNA samples from parents n/a). | M | White (Israel). | 11/15.6 | Poor linear growth (height –3.6 SDS at first visit), facial plethora, headaches, dorsocervical fat pad, weight gain (weight –0.8 SDS but BMI in 96th percentile), incidental finding of area of suspected ischemia in the right parietal lobe. | Midnight serum cortisol: 11.2 µg/dL; UFC: 229 µg/24 hours (4.1 × ULN); BIPSS: 27 central/peripheral and 15.6 right/left ACTH ratios. | 3 mm microadenoma (corticotropinoma), no extrasellar extension. | No LOH for CDKN1B variant. USP8 hotspot wild type. | Ketoconazole, TSS ×1, remission after surgery. | Not significant. | 17.3 |
BIPSS, bilateral inferior petrosal sinus sampling; CGH, comparative genomic hybridization; CRHST, CRH stimulation test; IHC, immunohistochemistry; LDDST, low-dose dexamethasone suppression test; LOH, loss of heterozygosity; PitNET, pituitary neuroendocrine tumor; TSS, transsphenoidal surgery; UFC, urinary free cortisol.
aAuxology and biochemistry taken before second surgery (data before first surgery not available).