Tumor Risk in DSD

*From August 2008 SPU Dialogues

For older Children:
2 to 6 yrs – 1/2 to 1 tab of senna po qd to bid; Max 1 tab po bid
6 to 12 yrs – 1 to 2 tabs of senna po qd to bid; Max 2 tabs po bid
> 12 yrs – 2 to 4 tabs of senna po qd to bid; Max 4 tabs po bid

JPS is inherited as an autosomal dominant trait. Approximately 75% of individuals with JPS have an affected parent; 25% of probands with JPS have no previous history of polyps in the family and may have the disorder as the result of a new gene mutation. Each child of an affected individual has a 50% chance of inheriting the mutation and developing JPS. Prenatal testing is available clinically for SMAD4 and BMPR1A mutations.

Differential Diagnosis:

1. PTEN hamartoma tumor syndromes (PHTS): Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are the two most common phenotypes of PHTS. They can be associated with juvenile polyps. CS is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s. BRRS is characterized by macrocephaly, intestinal polyposis, lipomas, and pigmented macules of the glans penis. PTEN is the only gene known to be associated with PTEN hamartoma tumor syndrome. Approximately 80% of individuals who meet the diagnostic criteria for CS and 60% of individuals with a clinical diagnosis of BRR have a detectable PTEN gene mutation. Inheritance is autosomal dominant.
2. Nevoid basal cell carcinoma syndrome (NBCCS). NBCCS is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas usually from the third decade onwards. About 60% have macrocephaly, forehead bossing with coarse facial features, and facial milia. Hamartomatous gastric polyps can occur. PTCH is the only gene known to be associated with NBCCS. Inheritance is autosomal dominant.
3. Peutz-Jeghers syndrome (PJS). Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. Peutz-Jeghers type hamartomatous polyps are most prevalent in the small intestine (jejunum, ileum, and duodenum, respectively), but also occur in the stomach and large bowel in the majority of affected individuals. LKB1 (STK11) is the only gene known to be associated with PJS. Inheritance is autosomal dominant.
4. Hereditary mixed polyposis syndrome (HMPS) (OMIM 601228). HMPS is characterized by atypical juvenile polyps, with mixed features of hamartomas and adenomas and a predisposition to cancer. The HMPS locus has been mapped to 15q13-q14 [Jaeger et al 2003].
5. Familial adenomatous polyposis (FAP). FAP is a colon cancer predisposition syndrome characterized by hundreds to thousands of precancerous adenomatous colonic polyps, beginning at a mean age of 16 years (range 7-36 years). The adenomatous polyps of FAP and juvenile polyps of JPS are histologically distinct. Extracolonic manifestations that are variably present include polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and associated cancers. APC is the only gene known to be associated with FAP. Inheritance is autosomal dominant.
6. Hereditary non-polyposis colon cancer (HNPCC). This diagnosis enters the differential of JPS as a result of the distribution of the polyps and the variable number of polyps served. However, the pathology of the polyps should be useful in distinguishing the two diagnoses. HNPCC is characterized by an increased risk of colon cancer and cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. HNPCC is known to be associated with mutations in five genes involved in mismatch repair: MSH2, MLH1, PMS1, PMS2, and MSH6. Inheritance is autosomal dominant.

In JPS, there are hamartomatous polyps throughout the GI tract: stomach, small intestine, colon, and rectum. The term “juvenile” refers to the type of polyp rather than to the age of onset of polyps. Most JPS pateints have some polyps by 20 years of age. The syndrome is quite variable with some patients having only four or five polyps in a lifetime, while other relatives may have more than a hundred. The most common symptom is painless rectal bleeding. Polyp prolapse via the rectum, crampy pain, and malnutrition are other frequent symptoms. Untreated polyps may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk of GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have been reported.

Familial Juvenile Polyposis can result from gene mutations. SMAD4 mutations account for 25 percent of Juvenile Polyposis families. In another report, the involved genes were BMPR1A and SMAD4. About 20% of individuals affected with JPS have mutations in the BMPR1A gene; approximately 20% have mutations in the SMAD4 gene. Sequence analysis of BMPR1A and SMAD4 is available on a clinical basis. Previously, it was thought that PTEN gene were a cause of JPS, but individuals with intestinal polyps and this gene probably have either Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome, phenotypes of the PTEN hamartoma tumor syndrome.

Standard management is routine colonoscopy with endoscopic polypectomy to reduce the risk of cancer, bleeding, or intestinal obstruction.
The most effective management is routine colonoscopy with endoscopic polypectomy. Early endoscopic polypectomy may reduce morbidity by reducing the risk of the cancer, bleeding, or intestinal obstruction. In some cases, removal of all or part of the colon or stomach may be necessary to alleviate symptoms and/or reduce cancer risk when a large number of polyps is present. The preferred procedures are subtotal colectomy with ileorectal anastamosis or proctocolectomy with ileoanal pouch procedure. The number of colonic or rectal polyps does not appear to correlate with the need for proctectomy. Juvenile Polyposis screening should include an upper and lower endoscopy q year, with removal of colonic polyps and any large upper intestinal polyps.

Anticipation (earlier age of onset and increased severity of symptoms with each successive generation) has been observed in some families with JPS, but could be due at least partially to better surveilance and recognition.

Surveillance
For individuals with JPS who have undergone surgical resection of bowel: endoscopic follow-up is required regardless of the surgical procedure because of the high rate of subsequent development of polyps in the rectum and the pouch [Oncel et al 2005].
For individuals with a SMAD4 or BMPR1A mutation identified by molecular genetic testing, individuals with a clinical diagnosis of juvenile polyposis syndrome (JPS), or individuals with a family history of JPS who have not undergone molecular genetic testing or whose molecular genetic test results were uninformative [Howe, Mitros et al 1998]:

Monitoring for rectal bleeding and/or anemia, abdominal pain, constipation, diarrhea, or change in stool size, shape, and/or color. These symptoms may warrant additional screening.
CBC, colonoscopy, and upper endoscopy screening should begin in the mid-teens (15 years) or at the time of initial symptoms, whichever is earlier.
If negative, screening should be repeated in three years.
If only one or a few polyps are identified, the polyps should be removed. Subsequently, screening should be done annually until no additional polyps are found, at which time screening every three years may resume.
If many polyps are identified, removal of the majority of the colon or stomach may be necessary. Subsequently, screening should be done annually until no additional polyps are found, at which time screening every three years may resume.

For individuals at risk for JPS who do not have the family-specific mutation [Howe, Mitros et al 1998]:

CBC and lower intestinal endoscopy should be performed at age 15 years as a baseline screening.
If negative, repeat screening every ten years until age 45 years, after which the standard American Cancer Society recommendations for colon cancer screening should be followed.
If polyps are identified, they need to be removed.
If polyps are identified, screening should be repeated in one year.

It is appropriate to consider repeating the molecular genetic testing or testing a different gene if the polyps identified are indeed juvenile polyps.

If there is a familial mutation, molecular genetic testing should be done on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance and intervention.

1. Grade I
   1. Subcapsular hematoma of less than 10% of surface area
   2. Capsular tear of less than 1 cm in depth
2. Grade II
   1.Subcapsular hematoma of 10-50% of surface area
   2. Intraparenchymal hematoma of less than 5 cm in diameter
   3. Laceration of 1-3 cm in depth and not involving trabecular vessels
3. Grade III
   1. Subcapsular hematoma of greater than 50% of surface area or expanding and ruptured subcapsular or parenchymal hematoma
   2. Intraparenchymal hematoma of greater than 5 cm or expanding
   3. Laceration of greater than 3 cm in depth or involving trabecular vessels
4. Grade IV – Laceration involving segmental or hilar vessels with devascularization of more than 25% of the spleen
5. Grade V – Shattered spleen or hilar vascular injury

The American Association for the Surgery of Trauma Organ Injury Severity Scale Liver grading system is as follows:

1. Grade I – Capsular avulsion; periportal blood tracking; superficial laceration less than 1-cm deep; subcapsular hematoma less than 1-cm thickness
2. Grade II – Laceration 1- to 3-cm deep; subcapsular/central hematoma 1- to 3-cm diameter
3. Grade III – Laceration greater than 3-cm deep; subcapsular/central hematoma greater than 3-cm diameter
4. Grade IV – Massive central or subcapsular hematoma greater than 10 cm; lobar tissue maceration or devascularization
5. Grade V – Bilobar tissue maceration or devascularization

1. Rectal exam with disimpaction if necessary.
2. Golytely – Administer the afternoon or evening before the operation.
3. Patients < 40 kg - give 25 cc/kg/hr
4. Patients > 40 kg – give 1 liter/hr (Repeat until rectal effluents are clear for a maximum of five hours. Small children will need a NG tube to take sufficient volumes of Golytely. If the child has a mucus fistula, administer 100 cc NS irrigations through the fistula until clear.)
5. Normal saline enemas until clear – usually 10cc/kg. Approximate volumes shown below:
6. PO Antibiotics a. Neomycin sulfate 25 mg/kg/dose given 12,11 & 6 hrs preop, and b. Erythromycin base 25 mg/kg/dose given 12,11 & 6 hrs preop.
7. D5 1/2 NS with 20 mEq kcl/l at 150% of maintenance
8. STAT electrolytes at 6:00 pm on night before OR & STAT at 6:00 am on day of OR.

Patients are frequently placed on D5LR on the day of surgery (especially abdominal cases) at 1 to 1-1/2 maintenance. IV fluids need to be changed over on post-op day 1 to D51/2NS with 20 mEq KCL/L and rates decreased to maintenance (assuming urine output is adequate). Please be sure that whatever fluid you give, that it has DEXTROSE. If a patient needs a bolus, LR or NS is used at 10-20 cc/kg. Maintenance IVF: We use the 4/2/1 rule. 4 cc/kg for first 10 kg, then 2 cc/kg for 10-20 kg, then 1 cc/kg over 20 kg. So a 14 kg child’s maintenance fluids would be 48 cc/hr. Monitor urine output closely.

Table: Mean Stretched Penile Length

ENERGY AND PROTEIN REQUIREMENTS

To Calculate total calories provided by your prescribed solution use this calculation: (divide each by kg)

__% Dextrose X ___cc/day / 100 / X 3.4= Kcals from dextrose

____cc Lipids X 2 = Kcals from fat

%AA X ____cc/day % 100 = gm of AA

*Exception: Newborn IV Fluids

1. 1st 24 hrs – 80 cc/kg/day of D1OW with 4.8 mEq Ca gluconate/250 cc
2. 2nd 24 hrs – 100 cc/kg/day of D10 1/4 NS + 5 meq KCl/250cc
3. After 48 hours – 120 cc/kg/day of D10 1/2 NS + 5 meq KC1/250

PRBC’s, FFP, or 5% Albumin – 10 cc/kg/dose
Whole blood – 10-20 cc/kg/dose
25% Albumin – 4 cc/kg/dose (1 gm/kg/dose)
Platelets – 3 units/kg

1. Peritoneal lavage – 10 cc/kg NS
2. Total blood volume is about 80 cc/kg
3. Oliguria is urine output <0.5 cc/kg/hr in infants